WO2023208018A1 - Substituted pyrimidine hydrazide compound, method for preparing same, and use thereof - Google Patents

Substituted pyrimidine hydrazide compound, method for preparing same, and use thereof Download PDF

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WO2023208018A1
WO2023208018A1 PCT/CN2023/090761 CN2023090761W WO2023208018A1 WO 2023208018 A1 WO2023208018 A1 WO 2023208018A1 CN 2023090761 W CN2023090761 W CN 2023090761W WO 2023208018 A1 WO2023208018 A1 WO 2023208018A1
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substituted
saturated
unsaturated
halogen
group
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张所明
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德明药泰生物技术（深圳）有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/04—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of biopharmaceuticals, and specifically relates to a type of substituted pyrimidine hydrazide compounds and their preparation methods and applications.
  • Aryl Hydrocarbon Receptor is a member of the bHLH-PAS (bHLH-PER-ARNT-SIM) subfamily of the basic helix-loop-helix (bHLH) superfamily. It is the only receptor in the bHLH-PAS family that can be activated by ligands [Murray et al., Nat.Rev.Cancer, 2014, 14(12), 801-814; Berstenetal., Nat.Rev.Cancer, 2013, 13 (12),827-841].
  • AHR existing in the cytoplasm can be stimulated by aromatic hydrocarbons (xenobiotics), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, tetrachlorodibenzo-p-dioxin), and then It moves into the nucleus and forms a heterodimer with the aryl hydrocarbon receptor nuclear transporter (ARNT), and the AHR/ARNT complex then interacts with the xenobiotic response element (XRE) upstream of the AHR regulatory gene.
  • XRE xenobiotic response element
  • the AHR pathway is one of the best understood mechanisms that binds environmental toxins and induces metabolism, such as the regulation of cytochrome CYP450 enzymes (such as CYP1A1, CYP1A2 and CYP1B1), which can metabolize environmental toxins [(Reyes et al., Science, 1992, 256 (5060), 1193-1195; Murray et al., Nat.Rev.Cancer, 2014, 14(12), 801-814].
  • cytochrome CYP450 enzymes such as CYP1A1, CYP1A2 and CYP1B1
  • Activation of AHR by environmental toxins has demonstrated the role of AHR in numerous cellular processes, such as Embryonic development, tumorigenesis and inflammation.
  • AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T-cells and NK cells, and plays an important role in immune regulation (Nguyen et al., Front .Immunol., 2014, 5, 511).
  • Classic exogenous AHR ligands such as TCDD induce profound immunosuppression, promote cancer occurrence and induce tumor growth [Gramatzkietal., Oncogene, 2009, 28(28), 2593-2605; Buietal. ,Oncogene,2009,28(41),3642-3651; Esseretal.,Trends.Immunol.,2009,30(9),447-454].
  • AHR regulates many key innate and adaptive immune responses. Studies have found that some AHR agonists promote the differentiation of Th17 cells (T-helper cells) and the secretion of IL-17. Other AHR agonists can induce the lateral differentiation of Th17 cells into Treg cells and enhance the suppressive activity of Treg [Quintana et al., Nature, 2008, 453(7191), 65-71; Mezrich et al., J. Immunol .,2010,185(6),3190-3198;].
  • AHR activation can inhibit the innate inflammatory response regulated by macrophages (such as reducing the expression of IL-1b, IL-6, IL-12 and TNFalpha induced by lipopolysaccharide (LPS, lipopolysaccharide)), and affect dendritic cells.
  • macrophages such as reducing the expression of IL-1b, IL-6, IL-12 and TNFalpha induced by lipopolysaccharide (LPS, lipopolysaccharide)
  • LPS lipopolysaccharide
  • antigen-presenting cells In order to establish an effective anti-tumor immune response, antigen-presenting cells (APCs) need to process and present tumor antigens, followed by activation of helper CD4+T-cells (Th) and cytotoxic CD8+ T-cells (cytotoxic CD8+T-cells, Tc), these cells work together to effectively kill tumor cells.
  • Tumor cells have developed several mechanisms to escape immunity regulated by Th and Tc cell lysis. One of them is the release of high concentrations of kynurenine and other potential AHR ligands in the tumor microenvironment (TME).
  • AHR ligands in the tumor microenvironment can lead to direct inhibition of APCs, Th, and Tc, while enhancing the recruitment, production, and activation of Treg, thereby further inhibiting the activities of Tc and Th.
  • TME tumor microenvironment
  • AHR inhibitors can block the AHR-dependent immune escape pathways used by malignant tumor cells, thereby restoring anti-tumor immunity.
  • an object of the present invention is to provide a class of substituted pyrimidine hydrazide compounds represented by the following formula I, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt:
  • a 1 , A 2 and A 3 are each independently CR A or N, and the substituent R A is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, saturated or unsaturated C 1 to C 8 alkyl substituted by halogen, hydroxyl, amino or R C , C 3 substituted by halogen, hydroxyl, amino or R C ⁇ C 8 cycloalkyl, saturated or unsaturated C 1 ⁇ C 8 alkoxy, C 3 ⁇ C 8 cycloalkoxy, saturated or unsaturated C 1 ⁇ C substituted by halogen, hydroxyl, amino or R C 8 alkoxy, C 3 ⁇ C 8 cycloalkoxy substituted by halogen, hydroxyl, amino or R C 8 alkoxy, C 3 ⁇ C 8 cycloalkoxy substituted by halogen, hydroxyl, amino or R C , -
  • a 4 is O, S, N, C or a connecting bond
  • a 5 , A 6 and A 7 are each independently O, S, N or C
  • each can be independently replaced by RB ;
  • RB is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -S(O) n Rc, saturated or unsaturated C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, saturated or unsaturated substituted by halogen, hydroxyl, amino or R C C 1 to C 8 alkyl, substituted by halogen , hydroxyl, amino or R C substituted C 3 ⁇ C 8 cycloalkyl, saturated or unsaturated C 1 ⁇ C 8 alkoxy, C 3 ⁇ C 8 cycloalkoxy, saturated or unsaturated substituted by halogen, Hydroxy, amino or R C substituted C 1 ⁇ C 8 alkoxy group, C 3 ⁇ C 8 cycloalkoxy group substituted by halogen, hydroxyl, amino or R C , saturated or unsaturated substituted or unsubstituted
  • the substituents R C and RD are each independently selected from hydrogen, halogen, cyano group, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated Saturated C 1 to C 6 alkyl substituted by halogen, hydroxyl, -S(O) n R E or NR F R G , C substituted by halogen, hydroxyl, -S(O) n R E or NR F R G 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 6 alkoxy, C 3 to C 6 cycloalkoxy, saturated or unsaturated by halogen, hydroxyl, -S(O) n R E Or NR FRG substituted C 1 ⁇ C 6 alkoxy group, C 3 ⁇ C 6 cycloalkoxy group substituted by halogen, hydroxyl, -S(O) n RE or NR FRG , where RE
  • R 3 is halogen, hydroxyl, -S(O) n Rc, NR C R D , saturated or unsaturated C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkoxy , C 3 ⁇ C 8 cycloalkoxy group, saturated or unsaturated C 1 ⁇ C 8 alkyl group substituted by halogen , hydroxyl, amino or R H , C 3 ⁇ C 8 cycloalkyl group, C 1 ⁇ C 8 alkyl group Oxygen group, C 3 to C 8 cycloalkoxy group, in which the substituent R H is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 6 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen,
  • R4 is hydrogen or deuterium.
  • n is an integer of 0, 1 or 2.
  • a 1 and A 3 are CRA , A 2 is N, and the substituent RA is each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkane group, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl, amino or R C , C 3 to C substituted by halogen, hydroxyl, amino or R C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy, saturated or unsaturated C 1 to C 3 alkane substituted by halogen, hydroxyl, amino or R C Oxygen group, C 3 to C 6 cycloalkoxy group substituted by halogen, hydroxyl, amino or R C , -S(O) n Rc, saturated or unsaturated substituted or unsubstituted C 1 to C 3 acyl group, NR
  • a 1 and A 3 are CRA , A 2 is N, and the substituent RA is hydrogen.
  • a 4 is N, C or a connecting bond
  • a 5 , A 6 and A 7 are each independently N or C
  • a 4 , A 5 , A 6 and A 7 are each independently connected to a substituent RB , and the substituent RB is each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -S(O) n Rc, Saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl, amino or R C , substituted by halogen, hydroxyl, Amino or R C -substituted C 3 ⁇ C 6 cycloalkyl, saturated or unsaturated C 1 ⁇ C 3 alkoxy, C 3 ⁇ C 6 cycloalkoxy, saturated or unsaturated C 1 to C 3 alkoxy substituted by halogen, hydroxyl, amino or R C , C 3 to C 6 cycloalkoxy substituted by halogen, hydroxyl, amino or R C , C 3 to C 6 cycloal
  • the substituents RC and RD are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or Unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl, -S(O) n R E or NR F R G , substituted by halogen, hydroxyl, -S(O) n R E or NR F R G C 3 ⁇ C 6 cycloalkyl, saturated or unsaturated C 1 ⁇ C 3 alkoxy, C 3 ⁇ C 6 cycloalkoxy, saturated or unsaturated by halogen, hydroxyl, -S(O) n R C 1 to C 3 alkoxy group substituted by E or NR F RG , C 3 to C 6 cycloalkoxy group substituted by halogen, hydroxyl, -S(O) n RE E or NR F RG , C 3
  • RE , RF and RG are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl , saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 to C 3 alkoxy Base, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 3 alkoxy group substituted by halogen, hydroxyl or amino group, C 3 to C 6 cycloalkoxy group substituted by halogen, hydroxyl group or amino group .
  • a 7 is C.
  • R 3 is halogen, -S(O) n Rc, NR C RD , saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group; saturated or unsaturated C 1 to C 6 alkyl group, C 3 to C 6 cycloalkyl group, C 1 to C 6 substituted by halogen, hydroxyl, amino or R H Alkoxy, C 3 to C 6 cycloalkoxy, wherein the substituent R H is selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 Cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 to C 3 alk
  • R 3 is halogen, -S(O) n Rc, NR C RD , saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 3 alkyl Oxygen group, C 3 ⁇ C 6 cycloalkoxy group; saturated or unsaturated C 1 ⁇ C 3 alkyl group, C 3 ⁇ C 6 cycloalkyl group, C 1 ⁇ C substituted by halogen, hydroxyl, amino or RF 3 alkoxy, C 3 ⁇ C 6 cycloalkoxy, wherein the substituent R H is selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 ⁇ C 3 alkyl, C 3 ⁇ C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, C 3 to C
  • R 1 and R 2 together with the N atom connecting them is selected from the following groups:
  • each of its optical isomers, prodrugs or pharmaceutically acceptable salts is selected from the following compounds:
  • another object of the present invention is to provide a pharmaceutical composition, said pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrimidine hydrazide compound according to the present invention, each of which is an optical isomer. , a prodrug or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or carrier.
  • another object of the present invention is to provide substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts for the preparation of AHR disorder inhibitors use in.
  • another object of the present invention is to provide substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts for the preparation of treatments for AHR disorders.
  • Applications related to oncology drugs are to provide substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts for the preparation of treatments for AHR disorders.
  • another object of the invention is to provide a method for treating tumors associated with AHR disorders, the method comprising administering an effective amount of a substituted pyrimidine according to the invention to a subject in need thereof Hydrazide compounds, their respective optical isomers, prodrugs or pharmaceutically acceptable salts or the pharmaceutical composition according to the present invention.
  • another object of the present invention is to provide a method for preparing the substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts, The method is as shown in reaction equation 1 below:
  • the carboxylic acid compound represented by formula III and the hydrazine compound represented by formula IV are subjected to a condensation reaction to obtain a substituted pyrimidine hydrazide compound represented by formula I;
  • the carboxylic acid compound represented by formula III is prepared according to one of the following methods:
  • C 1 to C 8 is intended to cover C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 1–8 , C 1–7 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2-8 , C 2-7 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3-8 , C 3-7 , C 3–6 , C 3–5 , C 3–4 , C 4-8 , C 4-7 , C 4–6 , C 4–5 , C 5-8 , C 5-7 , C 5–6 , C 6-8 , C 6-7 and C 7-8 .
  • Alkyl refers to a straight or branched chain saturated hydrocarbon radical having 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl”).
  • an alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”).
  • C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-propyl) Butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C 5 ) (for example, n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl group) and hexyl (C 6 ) (e.g., n-hexyl).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) ("substituted alkyl" ). In certain embodiments, alkyl is unsubstituted C 1-8 alkyl (eg, unsubstituted C 1 alkyl, such as -CH 3 ). In certain embodiments, alkyl is substituted C 1-8 alkyl (eg, substituted C 1 alkyl, such as -CF 3 ).
  • Alkoxy means a monovalent O alkyl group, wherein the alkyl moiety has the specified number of carbon atoms.
  • alkoxy groups typically contain 16 carbon atoms ("C1 to C6 alkoxy"), or 14 carbon atoms ("C1C4 alkoxy").
  • C1C4 alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy, etc.
  • each instance of alkoxy is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkoxy") or substituted with one or more substituents (“substituted alkoxy” ).
  • alkoxy is unsubstituted C1 to C6 alkoxy.
  • alkoxy is substituted C1 to C6 alkoxy.
  • Cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”) and zero heteroatoms in a non-aromatic ring system.
  • a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl group”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
  • a cycloalkyl group has 5 to 8 ring carbon atoms atom (“C 5-8 cycloalkyl”).
  • Exemplary C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentenyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl ( C 6 ), etc.
  • Exemplary C 3-8 cycloalkyl groups include, but are not limited to, the above-mentioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptyldi Alkenyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), etc.
  • each example of cycloalkyl is independently any is optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl").
  • cycloalkyl is unsubstituted C 3-8 cycloalkyl; in certain embodiments, cycloalkyl is substituted C 3-8 cycloalkyl.
  • Heterocycloalkyl means a group of 5 to 14 membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (" 5-14 membered heterocyclic group").
  • the point of attachment may be a carbon atom or a nitrogen atom, as long as the valency permits.
  • Heterocyclic groups may be monocyclic ("monocyclic heterocyclyl”) or fused, bridged or spiro ring systems, such as bicyclic systems (“bicyclic heterocyclyl”), and may be saturated or may be partially Unsaturated.
  • Heterocyclyl group also includes ring systems in which a heterocycle as defined above is fused to one or more cycloalkyl groups (where the point of attachment is on the cycloalkyl group or heterocycle), or in which a heterocycle as defined above is fused
  • each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted with one or more substituents ("substituted heterocycloalkyl").
  • Cycloalkyl refers to any substituents.
  • heterocycloalkyl is unsubstituted 5-14 membered heterocycloalkyl.
  • Aryl or “aromatic ring” or “aromatic ring group” refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic ring) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. Ring) A group of 4n+2 aromatic ring systems (eg, having 6, 10, or 14 ⁇ electrons shared in a cyclic array) ("C 6-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms ("C 10 aryl”; for example, naphthyl, such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms ("C 14 aryl”; for example, anthracenyl).
  • Aryl also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the aromatic ring, and in this case, the carbon atom The number continues to refer to the number of carbon atoms in the aromatic ring system.
  • each instance of aryl is independently optionally substituted, ie, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").
  • aryl is unsubstituted C 6-14 aryl.
  • aryl is substituted C 6-14 aryl.
  • Heteroaryl is a 5-14 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl”).
  • heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-8 membered heteroaryl").
  • heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-6 membered heteroaryl").
  • a 5-6 membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • a 5-6 membered heteroaryl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • a 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl” ).
  • heteroaryl is unsubstituted 5-14 membered heteroaryl.
  • heteroaryl is substituted 5-14 membered heteroaryl.
  • Halogen refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).
  • Substituted or “optionally substituted” means that an atom, such as a hydrogen atom, in the group is substituted.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted (e.g., "substituted” alkyl, "substituted” cycloalkyl, “substituted” heterocycloalkyl radical, "substituted” aryl, or "substituted” heteroaryl).
  • a "substituted” group has a substituent at one or more substitutable positions on the group, and when more than one position in any given structure is substituted, the substituent is present at each The location is the same or different.
  • substituted is intended to include substitution with all permissible substituents of organic compounds, any substituent described herein that results in the formation of a stable compound. This disclosure contemplates any and all of these combinations to obtain stable compounds.
  • a heteroatom such as nitrogen may have a hydrogen substituent and/or any suitable substituent as described herein that satisfies the valency of the heteroatom and results in the formation of a stable moiety.
  • the substituents are carbon atom substituents.
  • the substituents are nitrogen atom substituents.
  • the substituents are oxygen atom substituents.
  • the substituent is a sulfur atom substituent.
  • “Unsaturated” or “partially unsaturated” refers to a group containing at least one double or triple bond. “Partially unsaturated” ring systems are also intended to encompass rings having multiple sites of unsaturation, but are not intended to include aromatic groups (eg, aryl or heteroaryl). Likewise, “saturated” refers to a group that contains no double or triple bonds, that is, all single bonds.
  • RA can be "saturated or unsaturated C 1 to C 8 alkyl” or “saturated or unsaturated C 1 to C substituted by halogen, hydroxyl, amino or R C 8 alkyl", and the substituent Rc can be defined as "hydrogen, halogen, hydroxyl, amino", etc.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts examples include inorganic acid salts and organic acid salts
  • the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid , hydrogen sulfate, hydriodic acid, phosphorous acid, etc.
  • the organic acids include benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, Oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methane sulfonic acid
  • the modifier term "about” refers to numerical variations that may occur, e.g., through routine testing and handling; through inadvertent errors in such testing and handling; through variations in the manufacture, source, or purity of the ingredients used in the invention. Difference; etc.
  • “about” a particular value also includes that particular value, for example, about 10% includes 10%.
  • the claims include equivalents of the recited quantities. In one embodiment, the term “about” means within 20% of the reported value.
  • the term “treating” means eliminating, alleviating or ameliorating a disease or condition and/or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition or symptoms associated with it.
  • the term “treatment” and the like may include “preventive treatment” which refers to reducing the recurrence of a disease or condition in a subject who does not have or is at risk of developing or susceptible to the disease or condition or the recurrence of the disease or condition. The possibility of development or recurrence of a previously controlled disease or condition.
  • treatment and synonyms contemplate the administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.
  • the term "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect.
  • the "effective amount” of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • Diseases related to the AHR disorder according to the present invention include, but are not limited to, tumors.
  • step 2 Dissolve the mixture of II-A and III-A obtained in step 2) in a mixed solvent of methanol/tetrahydrofuran/water (1/1/1), add lithium hydroxide monohydrate (4 equivalents), and stir at room temperature for 5 hours. Neutralize to pH 7 with 1N hydrochloric acid, concentrate to a small volume under reduced pressure, filter, wash the solid with ethanol-water (1:1), and dry to obtain intermediate III-A (205 mg, 79%), LC/MS (ESI) :m/z346[M+1] + , 344[M-1] + .
  • Step 1) Preparation of intermediate XV-Y: Prepare according to method E (see step 1 of method E).
  • Step 3) Preparation of intermediate IV-2: The method is the same as that of compound IV-1 in step 3) in Example 7, and the yield is 90%.
  • Compound 67 was prepared according to a method similar to Example 13. Compound 67 was obtained by reacting compound 10 with methanesulfonyl chloride. The yield was 41%. LC/MS (ESI): m/z 480 [M+1] + .
  • Compound 68 was prepared in a similar manner to Example 13. Compound 68 was obtained by reacting compound 10 with nicotine chloride hydrochloride. The yield was 84%. LC/MS (ESI): m/z 507 [M+1] + .
  • the test used the human liver cancer HepG2 cell line that endogenously expresses AHR protein (provided by the Stem Cell Bank of the Chinese Academy of Sciences).
  • AHR can bind to a sequence called a xenobiotic response element (XRE) on the CYP1A1 enhancer and trigger CYP1A1 gene expression.
  • XRE xenobiotic response element
  • the 1200 bp (-1143 to +57) regulatory sequence upstream of the CYP1A1 gene promoter was synthesized and inserted into a plasmid vector containing firefly luciferase.
  • the plasmid was then linearized by single enzyme digestion and transfected into HepG2 cells via lipofectamine 3000.
  • the transfected HepG2 cells were screened with puromycin to obtain stable expression cell lines.
  • AHR agonists such as L-Kynurenine, Kynurenic acid, indirubin, TCDD, ITE (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester
  • Expression of firefly luciferase is elicited while cells are treated with different concentrations of compounds, and the inhibition of luciferase expression by the compounds is measured.
  • MEM Minimum Eagle's medium
  • MEM medium was supplemented with 1mM sodium pyruvate, 2mM GlutaMax, 1 ⁇ non-essential amino acids, 10% Australian fetal calf serum, 100U/mL penicillin and 5ug/mL puromycin.
  • HepG2 cells were seeded into 96-well plates at a density of 5 to 8 ⁇ 10 4 /well and grown for 24 to 48 h to reach ⁇ 90% confluence before drug treatment (the culture medium did not contain puromyces white).
  • each compound was tested repeatedly for each group.
  • the well signal with a compound concentration of 0 was taken as 100%, and the cell signal with untreated agonist was taken as 0.
  • the AHR activity inhibition percentage at different compound concentrations was calculated in turn.
  • the average value of 2 sets of repeated data is calculated by nonlinear fitting according to the formula Calculate the IC 50 corresponding to the compound, where y is the percent inhibition and x is the concentration of the corresponding compound.
  • the IC 50 of each compound is shown in Table 2, where A means IC 50 ⁇ 500nM, B means 500nM ⁇ IC 50 ⁇ 1.0 ⁇ M, C means 1 ⁇ M ⁇ IC 50 ⁇ 5.0 ⁇ M, and D means IC 50 >5.0 ⁇ M.
  • each of the above compounds can bind to AHR and inhibit those functions and signaling pathways controlled by AHR, thereby affecting the growth and proliferation of cancer cells and the invasiveness of tumor cells. Therefore, the compounds represented by Formula I of the present invention It can be used to inhibit the growth of cancer cells and inhibit the metastasis and invasion of tumor cells.

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Abstract

The present invention provides a substituted pyrimidine hydrazide compound represented by formula (I) or an optical isomer, a prodrug or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the substituted pyrimidine hydrazide compound, and use thereof in preparing an AHR disorder inhibitor. The substituted pyrimidine hydrazide compound according to the present invention can bind to AHR and inhibit the functions and signaling pathways controlled by AHR, thereby affecting the growth and proliferation of cancer cells and the invasiveness of tumor cells. Therefore, the substituted pyrimidine hydrazide compound of the present invention can be used for inhibiting the growth of cancer cells and inhibiting the metastasis and invasion of tumor cells.

Description

取代嘧啶酰肼类化合物及其制备方法和应用Substituted pyrimidine hydrazide compounds and their preparation methods and applications 技术领域Technical field
本发明属于生物制药技术领域，具体涉及一类取代嘧啶酰肼类化合物及其制备方法和应用。The invention belongs to the technical field of biopharmaceuticals, and specifically relates to a type of substituted pyrimidine hydrazide compounds and their preparation methods and applications.
背景技术Background technique
芳香烃受体(AHR，Aryl Hydrocarbon Receptor)是碱性螺旋-环-螺旋(bHLH，basic helix-loop-helix)超家族的亚家族bHLH-PAS(bHLH-PER-ARNT-SIM)成员之一，是bHLH-PAS家族中唯一可以被配体激活的受体[Murray et al.,Nat.Rev.Cancer,2014,14(12),801-814；Berstenetal.,Nat.Rev.Cancer,2013,13(12),827-841]。存在于胞浆中的AHR能够接受芳香烃类异质物(xenobiotic)，如2,3,7,8-四氯二苯并对二恶英(TCDD，tetrachlorodibenzo-p-dioxin)的刺激，然后迁入细胞核与芳香烃受体核转运体(ARNT，ArylHydrocarbonReceptorNuclearTranslocator)形成一个异二聚体，AHR/ARNT复合物接着与AHR调控基因上游的异物质遗传应答元件(XRE，xenobiotic response element)相互作用，从而调控相应基因的转录；AHR也可以激活非XRE依赖的蛋白-蛋白交互作用通路。Aryl Hydrocarbon Receptor (AHR) is a member of the bHLH-PAS (bHLH-PER-ARNT-SIM) subfamily of the basic helix-loop-helix (bHLH) superfamily. It is the only receptor in the bHLH-PAS family that can be activated by ligands [Murray et al., Nat.Rev.Cancer, 2014, 14(12), 801-814; Berstenetal., Nat.Rev.Cancer, 2013, 13 (12),827-841]. AHR existing in the cytoplasm can be stimulated by aromatic hydrocarbons (xenobiotics), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, tetrachlorodibenzo-p-dioxin), and then It moves into the nucleus and forms a heterodimer with the aryl hydrocarbon receptor nuclear transporter (ARNT), and the AHR/ARNT complex then interacts with the xenobiotic response element (XRE) upstream of the AHR regulatory gene. Thereby regulating the transcription of corresponding genes; AHR can also activate XRE-independent protein-protein interaction pathways.
AHR通路是了解最多的结合环境毒素并且诱导代谢机制之一，如调控的细胞色素CYP450酶(如CYP1A1，CYP1A2和CYP1B1)，这些酶可以代谢环境毒素[(Reyes et al.,Science,1992,256(5060),1193-1195；Murray et al.，Nat.Rev.Cancer,2014,14(12),801-814]。通过环境毒素对AHR的激活已经证明AHR在众多细胞过程中的作用，例如胚胎发育、肿瘤发生及炎症。AHR在免疫***许多细胞中都有表达，包括树突细胞、巨噬细胞、T-细胞和NK细胞，而且在免疫调节中起重要作用(Nguyen et al.,Front.Immunol.,2014,5,511)。经典的外源性AHR配体TCDD等诱导深度免疫抑制、促进癌症发生及诱导肿瘤生长[Gramatzkietal.,Oncogene,2009,28(28),2593-2605；Buietal.,Oncogene,2009,28(41),3642-3651；Esseretal.,Trends.Immunol.,2009,30(9),447-454]。The AHR pathway is one of the best understood mechanisms that binds environmental toxins and induces metabolism, such as the regulation of cytochrome CYP450 enzymes (such as CYP1A1, CYP1A2 and CYP1B1), which can metabolize environmental toxins [(Reyes et al., Science, 1992, 256 (5060), 1193-1195; Murray et al., Nat.Rev.Cancer, 2014, 14(12), 801-814]. Activation of AHR by environmental toxins has demonstrated the role of AHR in numerous cellular processes, such as Embryonic development, tumorigenesis and inflammation. AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T-cells and NK cells, and plays an important role in immune regulation (Nguyen et al., Front .Immunol., 2014, 5, 511). Classic exogenous AHR ligands such as TCDD induce profound immunosuppression, promote cancer occurrence and induce tumor growth [Gramatzkietal., Oncogene, 2009, 28(28), 2593-2605; Buietal. ,Oncogene,2009,28(41),3642-3651; Esseretal.,Trends.Immunol.,2009,30(9),447-454].
通过XRE-依赖性或非依赖性活性，AHR调节许多关键的先天和自适应免疫反应。研究发现一些AHR激动剂促进产生Th17细胞(T-helper cells)分化及IL-17的分泌。而另一些AHR的激动剂可以诱导Th17细胞向Treg细胞的横向分化，加强Treg的抑制活性[Quintana et al.,Nature,2008,453(7191),65-71；Mezrich et al.,J.Immunol.,2010,185(6),3190-3198；]。研究证明AHR激活可对巨噬细胞调控的先天炎症反应产生抑制(例如减少脂多糖(LPS，lipopolysaccharide)诱导的IL-1b，IL-6，IL-12及TNFalpha表达)，及对树突细胞的抑制(降低树突细胞的活化及促进IL-10的表达)[Kimura et al.,J.Exp.Med.,2009,206(9),2027-2035；Wang et al.,Clin.Exp.Immunol.,2014,177(2),521-530；Weiet al.,Lab.Invest.,2014,94(5),528-535；Nguyen et al.,Proc.Natl.Acad.Sci.USA,2010,107(46),19961-19966]。Through XRE-dependent or -independent activities, AHR regulates many key innate and adaptive immune responses. Studies have found that some AHR agonists promote the differentiation of Th17 cells (T-helper cells) and the secretion of IL-17. Other AHR agonists can induce the lateral differentiation of Th17 cells into Treg cells and enhance the suppressive activity of Treg [Quintana et al., Nature, 2008, 453(7191), 65-71; Mezrich et al., J. Immunol .,2010,185(6),3190-3198;]. Studies have shown that AHR activation can inhibit the innate inflammatory response regulated by macrophages (such as reducing the expression of IL-1b, IL-6, IL-12 and TNFalpha induced by lipopolysaccharide (LPS, lipopolysaccharide)), and affect dendritic cells. Inhibition (reduces the activation of dendritic cells and promotes the expression of IL-10) [Kimura et al., J.Exp.Med., 2009, 206(9), 2027-2035; Wang et al., Clin.Exp.Immunol .,2014,177(2),521-530; Weiet al.,Lab.Invest.,2014,94(5),528-535;Nguyen et al.,Proc.Natl.Acad.Sci.USA,2010, 107(46),19961-19966].
为了建立有效的抗肿瘤免疫反应，抗原呈递细胞(APCs，antigen presenting cells)需要处理、呈递肿瘤抗原，接着激活辅助性CD4+T-细胞(helper CD4+T-cells，Th)和细胞毒性CD8+T-细胞(cytotoxic CD8+T-cells,Tc)，这些细胞协同作用有效杀灭肿瘤细胞。肿瘤细胞已经发展了几种机制逃逸Th和Tc细胞溶解调控的免疫。其中之一就是在肿瘤微环境(TME，tumor microenvironment)中释放高浓度的犬尿氨酸(kynurenine)及其它潜在的AHR配体。In order to establish an effective anti-tumor immune response, antigen-presenting cells (APCs) need to process and present tumor antigens, followed by activation of helper CD4+T-cells (Th) and cytotoxic CD8+ T-cells (cytotoxic CD8+T-cells, Tc), these cells work together to effectively kill tumor cells. Tumor cells have developed several mechanisms to escape immunity regulated by Th and Tc cell lysis. One of them is the release of high concentrations of kynurenine and other potential AHR ligands in the tumor microenvironment (TME).
肿瘤微环境(TME)中高浓度的AHR配体可导致直接抑制APCs、Th和Tc，同时增强Treg的招募、产生和活化，从而进一步抑制Tc和Th的活性。肿瘤通过这些机理能 够逃避抗肿瘤免疫应答[Opitz et al.,Nature,2011,478(7368),197-203]。所以，AHR抑制剂可以阻断恶性肿瘤细胞采用的AHR依赖性免疫逃逸通路，从而恢复抗肿瘤免疫。High concentrations of AHR ligands in the tumor microenvironment (TME) can lead to direct inhibition of APCs, Th, and Tc, while enhancing the recruitment, production, and activation of Treg, thereby further inhibiting the activities of Tc and Th. Through these mechanisms, tumors can enough to evade anti-tumor immune responses [Opitz et al., Nature, 2011, 478(7368), 197-203]. Therefore, AHR inhibitors can block the AHR-dependent immune escape pathways used by malignant tumor cells, thereby restoring anti-tumor immunity.
近年对肿瘤免疫生物学的研究表明，恶性肿瘤细胞采用多种免疫逃逸机制逃避免疫***。临床前和临床研究证明，通过治疗应用的组合(如免疫检查点抑制和疫苗)阻断或者加强这些机制，可以提供抗肿瘤免疫应答的最佳恢复。研究数据显示不仅单独使用AHR调节剂会恢复抗肿瘤免疫，因为AHR信号通路的独特性，可以预期AHR抑制剂与其他肿瘤免疫疗法联合，甚至与其它治疗方法协同作用将加强免疫治疗应答。临床上目前单独免疫检查点抑制剂的应答率还未达到较高水平，因此开发新的抗肿瘤免疫调控靶点对肿瘤的治疗有着重要意义，AHR作为一个充满潜力的靶点，研发相应的抑制剂为新型抗肿瘤疗法提供了新的空间。Recent research on tumor immunobiology has shown that malignant tumor cells use a variety of immune evasion mechanisms to evade the immune system. Preclinical and clinical studies have demonstrated that blocking or enhancing these mechanisms through a combination of therapeutic applications, such as immune checkpoint inhibition and vaccines, can provide optimal restoration of anti-tumor immune responses. Research data show that not only the use of AHR modulators alone will restore anti-tumor immunity, but because of the uniqueness of the AHR signaling pathway, it is expected that AHR inhibitors combined with other tumor immunotherapies, or even synergistically with other treatments, will enhance the immunotherapy response. Clinically, the response rate of immune checkpoint inhibitors alone has not yet reached a high level. Therefore, the development of new anti-tumor immune regulatory targets is of great significance for the treatment of tumors. As a target full of potential, AHR needs to be developed to inhibit Agents provide new space for new anti-tumor therapies.
发明内容Contents of the invention
因此，根据本发明的第一个方面，本发明的一个目的在于提供一类由以下式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐：
Therefore, according to the first aspect of the present invention, an object of the present invention is to provide a class of substituted pyrimidine hydrazide compounds represented by the following formula I, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt:
其中，in,
A1、A2和A3各自独立地为CRA或N，所述取代基RA各自独立地选自氢，氘，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C8烷基、C3～C8环烷基，饱和或不饱和的被卤素、羟基、氨基或RC取代的C1～C8烷基，被卤素、羟基、氨基或RC取代的C3～C8环烷基，饱和或不饱和C1～C8烷氧基、C3～C8环烷氧基，饱和或不饱和的被卤素、羟基、氨基或RC取代的C1～C8烷氧基，被卤素、羟基、氨基或RC取代的C3～C8环烷氧基，-S(O)nRc，饱和或不饱和的取代或未取代的C1～C8酰基，NRCRD，A 1 , A 2 and A 3 are each independently CR A or N, and the substituent R A is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, saturated or unsaturated C 1 to C 8 alkyl substituted by halogen, hydroxyl, amino or R C , C 3 substituted by halogen, hydroxyl, amino or R C ~C 8 cycloalkyl, saturated or unsaturated C 1 ~ C 8 alkoxy, C 3 ~ C 8 cycloalkoxy, saturated or unsaturated C 1 ~ C substituted by halogen, hydroxyl, amino or R C 8 alkoxy, C 3 ~ C 8 cycloalkoxy substituted by halogen, hydroxyl, amino or R C , -S(O) n Rc, saturated or unsaturated substituted or unsubstituted C 1 ~ C 8 acyl ,NR C R D ,
A4为O、S、N、C或连接键，A5、A6和A7各自独立地为O、S、N或C；并且A 4 is O, S, N, C or a connecting bond, and A 5 , A 6 and A 7 are each independently O, S, N or C; and
当A4、A5、A6和A7为N或C时，各自可以独立地被RB取代；RB各自独立地选自氢，氘，卤素，氰基，羟基，-S(O)nRc，饱和或不饱和的C1～C8烷基、C3～C8环烷基，饱和或不饱和的被卤素、羟基、氨基或RC取代C1～C8烷基，被卤素、羟基、氨基或RC取代的C3～C8环烷基，饱和或不饱和的C1～C8烷氧基、C3～C8环烷氧基，饱和或不饱和的被卤素、羟基、氨基或RC取代C1～C8烷氧基，被卤素、羟基、氨基或RC取代的C3～C8环烷氧基，饱和或不饱和的取代或未取代的C1～C8酰基，饱和或不饱和的取代或未取代的C1～C8烷氧基羰基，饱和或不饱和的取代或未取代的C1～C8烷胺基羰基，NRCRD，When A 4 , A 5 , A 6 and A 7 are N or C, each can be independently replaced by RB ; RB is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -S(O) n Rc, saturated or unsaturated C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, saturated or unsaturated substituted by halogen, hydroxyl, amino or R C C 1 to C 8 alkyl, substituted by halogen , hydroxyl, amino or R C substituted C 3 ~ C 8 cycloalkyl, saturated or unsaturated C 1 ~ C 8 alkoxy, C 3 ~ C 8 cycloalkoxy, saturated or unsaturated substituted by halogen, Hydroxy, amino or R C substituted C 1 ~ C 8 alkoxy group, C 3 ~ C 8 cycloalkoxy group substituted by halogen, hydroxyl, amino or R C , saturated or unsaturated substituted or unsubstituted C 1 ~ C 8 acyl, saturated or unsaturated substituted or unsubstituted C 1 to C 8 alkoxycarbonyl, saturated or unsaturated substituted or unsubstituted C 1 to C 8 alkylaminocarbonyl, NR C R D ,
其中，取代基RC和RD各自独立地选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C6烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基、-S(O)nRE或NRFRG取代C1～C6烷基，被卤素、羟基、-S(O)nRE或NRFRG取代的C3～C6环烷基，饱和或不饱和的C1～C6烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基、-S(O)nRE或NRFRG取代C1～C6烷氧基，被卤素、羟基、-S(O)nRE或NRFRG取代的C3～C6环烷氧基，其中RE、RF和RG各自独立地选自氢，氘，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C6烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基或氨基取代C1～C6烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C6烷氧基，C3～C6环烷氧基，饱 和或不饱和的被卤素、羟基或氨基取代C1～C6烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基；Among them, the substituents R C and RD are each independently selected from hydrogen, halogen, cyano group, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated Saturated C 1 to C 6 alkyl substituted by halogen, hydroxyl, -S(O) n R E or NR F R G , C substituted by halogen, hydroxyl, -S(O) n R E or NR F R G 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 6 alkoxy, C 3 to C 6 cycloalkoxy, saturated or unsaturated by halogen, hydroxyl, -S(O) n R E Or NR FRG substituted C 1 ~ C 6 alkoxy group, C 3 ~ C 6 cycloalkoxy group substituted by halogen, hydroxyl, -S(O) n RE or NR FRG , where RE , R F and R G are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 6 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 to C 6 alkoxy, C 3 to C 6 cycloalkoxy, saturated And or unsaturated C 1 to C 6 alkoxy group substituted by halogen, hydroxyl or amino group, C 3 to C 6 cycloalkoxy group substituted by halogen, hydroxyl group or amino group;
R1和R2各自独立地为氢，饱和或不饱和的取代或未取代的C1～C8烷基、饱和或不饱和的取代或未取代的C3～C8环烷基、-OC(＝O)C1-8烷基、-OC(＝O)C3～C8环烷基、-C(＝O)OC1-8烷基、-C(＝O)OC3～C8环烷基、-S(O)nRc、饱和或不饱和的取代或未取代的C1～C8磺酰基、饱和或不饱和的取代或未取代的C1～C8酰基、C6～C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或杂芳基，其中所述“取代”是指选择性地含有1至4个选自羟基、卤素、氰基、磺酰基、氨基、-S(O)nRc、NRCRD、饱和或不饱和的C1～C8烷基、饱和或不饱和的C3～C8环烷基、饱和或不饱和的C1～C8烷氧基、饱和或不饱和的C3～C8环烷氧基、-OC(＝O)C1-8烷基、-OC(＝O)C3～C8环烷基、-C(＝O)OC1-8烷基、-C(＝O)OC3～C8环烷基、饱和或不饱和的C1～C8磺酰基、饱和或不饱和的C1～C8酰基、饱和或不饱和的C1～C8烷氧基羰基、C6～C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或杂芳基的取代基；R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 to C 8 alkyl, saturated or unsaturated substituted or unsubstituted C 3 to C 8 cycloalkyl, -OC (=O)C 1-8 alkyl, -OC(=O)C 3 to C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 to C 8 Cycloalkyl, -S(O) n Rc, saturated or unsaturated substituted or unsubstituted C 1 to C 8 sulfonyl group, saturated or unsaturated substituted or unsubstituted C 1 to C 8 acyl group, C 6 ~ C 14 aryl, 4 to 14 membered heterocycloalkyl or heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" means optionally containing 1 to 4 Selected from hydroxyl, halogen, cyano, sulfonyl, amino, -S(O) n Rc, NR CRD , saturated or unsaturated C 1 to C 8 alkyl, saturated or unsaturated C 3 to C 8 Cycloalkyl, saturated or unsaturated C 1 to C 8 alkoxy, saturated or unsaturated C 3 to C 8 cycloalkoxy, -OC(=O)C 1-8 alkyl, -OC(= O)C 3 to C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 to C 8 cycloalkyl, saturated or unsaturated C 1 to C 8 sulfonyl Acyl group, saturated or unsaturated C 1 to C 8 acyl group, saturated or unsaturated C 1 to C 8 alkoxycarbonyl group, C 6 to C 14 aryl group, containing 1 to 3 selected from N, O and S 4 to 14 membered heterocycloalkyl or heteroaryl substituents of heteroatoms;
或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的4至14元杂环烷基，取代或未取代的含有1至3个选自N、O和S的杂原子的5至14元杂芳基，其中所述“取代”是指选择性地含有1至4个选自氘，羟基，卤素，氰基，磺酰基，氨基，-S(O)nRc，NRCRD，C1～C8烷基，C3～C8环烷基，C1～C8烷氧基，C3～C8环烷氧基，-OC(＝O)C1-8烷基，-OC(＝O)C3～C8环烷基，-C(＝O)OC1-8烷基，-C(＝O)OC3～C8环烷基，被卤素、羟基、氨基或RH取代C1～C8烷基、C3～C8环烷基、C1～C8烷氧基、C3～C8环烷氧基的取代基，其中RH选自氢，氘，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C6烷基，C3～C6环烷基，-S(O)nRc，NRCRD，饱和或不饱和的被氘、卤素、羟基或氨基取代C1～C6烷基，被氘、卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C6烷氧基，C3～C6环烷氧基，饱和或不饱和的被氘、卤素、羟基或氨基取代C1～C6烷氧基，被氘、卤素、羟基或氨基取代的C3～C6环烷氧基；Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 4 to 14 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 14-membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to optionally containing 1 to 4 selected from deuterium, hydroxyl, halogen, and cyano groups, Sulfonyl, amino, -S(O) n Rc, NR C R D , C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkoxy, C 3 to C 8 ring Alkoxy group, -OC(=O)C 1-8 alkyl group, -OC(=O)C 3 to C 8 cycloalkyl group, -C(=O)OC 1-8 alkyl group, -C(=O )OC 3 ~ C 8 cycloalkyl, substituted by halogen, hydroxyl, amino or R H C 1 ~ C 8 alkyl, C 3 ~ C 8 cycloalkyl, C 1 ~ C 8 alkoxy, C 3 ~ C 8 cycloalkoxy substituents, wherein R H is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, - S(O) n Rc, NR C R D , saturated or unsaturated C 1 to C 6 alkyl group substituted by deuterium, halogen, hydroxyl or amino group, C 3 to C 6 ring substituted by deuterium, halogen, hydroxyl group or amino group Alkyl group, saturated or unsaturated C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 6 alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, C 3 to C 6 cycloalkoxy substituted by deuterium, halogen, hydroxyl or amino;
R3为卤素，羟基，-S(O)nRc，NRCRD，饱和或不饱和的C1～C8烷基、C3～C8环烷基、C1～C8烷氧基、C3～C8环烷氧基，饱和或不饱和的被卤素、羟基、氨基或RH取代的C1～C8烷基、C3～C8环烷基、C1～C8烷氧基、C3～C8环烷氧基，其中取代基RH选自氢，氘，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C6烷基、C3～C6环烷基，饱和或不饱和的被卤素、羟基或氨基取代C1～C6烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C6烷氧基、C3～C6环烷氧基，饱和或不饱和的被卤素、羟基或氨基取代C1～C6烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基。R 3 is halogen, hydroxyl, -S(O) n Rc, NR C R D , saturated or unsaturated C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkoxy , C 3 ~ C 8 cycloalkoxy group, saturated or unsaturated C 1 ~ C 8 alkyl group substituted by halogen , hydroxyl, amino or R H , C 3 ~ C 8 cycloalkyl group, C 1 ~ C 8 alkyl group Oxygen group, C 3 to C 8 cycloalkoxy group, in which the substituent R H is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 6 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 to C 6 alkoxy, C 3 to C 6 cycloalkoxy, saturated or unsaturated C 1 to C 6 alkoxy, substituted by halogen, hydroxyl or amino, C 3 to C 6 substituted by halogen, hydroxyl or amino Cycloalkoxy.
R4为氢或氘。R4 is hydrogen or deuterium.
n为0、1或2的整数。n is an integer of 0, 1 or 2.
优选地，A1和A3为CRA，A2为N，所述取代基RA各自独立地选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基、C3～C6环烷基，饱和或不饱和的被卤素、羟基、氨基或RC取代的C1～C3烷基，被卤素、羟基、氨基或RC取代的C3～C6环烷基，饱和或不饱和C1～C3烷氧基、C3～C6环烷氧基，饱和或不饱和的被卤素、羟基、氨基或RC取代的C1～C3烷氧基，被卤素、羟基、氨基或RC取代的C3～C6环烷氧基，-S(O)nRc，饱和或不饱和的取代或未取代的C1～C3酰基，NRCRD；Preferably, A 1 and A 3 are CRA , A 2 is N, and the substituent RA is each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkane group, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl, amino or R C , C 3 to C substituted by halogen, hydroxyl, amino or R C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy, saturated or unsaturated C 1 to C 3 alkane substituted by halogen, hydroxyl, amino or R C Oxygen group, C 3 to C 6 cycloalkoxy group substituted by halogen, hydroxyl, amino or R C , -S(O) n Rc, saturated or unsaturated substituted or unsubstituted C 1 to C 3 acyl group, NR C R D ;
更优选地，A1和A3为CRA，A2为N，并且所述取代基RA为氢。More preferably, A 1 and A 3 are CRA , A 2 is N, and the substituent RA is hydrogen.
优选地，A4为N、C或连接键，A5、A6和A7各自独立地为N或C，并且Preferably, A 4 is N, C or a connecting bond, A 5 , A 6 and A 7 are each independently N or C, and
A4、A5、A6和A7各自独立地连接取代基RB，所述取代基RB各自独立地选自氢，卤素，氰基，羟基，氨基，-S(O)nRc，饱和或不饱和的C1～C3烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基、氨基或RC取代C1～C3烷基，被卤素、羟基、氨基或RC取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的 被卤素、羟基、氨基或RC取代C1～C3烷氧基，被卤素、羟基、氨基或R’取代的C3～C6环烷氧基，饱和或不饱和的取代或未取代的C1～C3酰基，饱和或不饱和的取代或未取代的C1～C3烷氧基羰基，NRCRD；A 4 , A 5 , A 6 and A 7 are each independently connected to a substituent RB , and the substituent RB is each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -S(O) n Rc, Saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl, amino or R C , substituted by halogen, hydroxyl, Amino or R C -substituted C 3 ~ C 6 cycloalkyl, saturated or unsaturated C 1 ~ C 3 alkoxy, C 3 ~ C 6 cycloalkoxy, saturated or unsaturated C 1 to C 3 alkoxy substituted by halogen, hydroxyl, amino or R C , C 3 to C 6 cycloalkoxy substituted by halogen, hydroxyl, amino or R', saturated or unsaturated substituted or unsubstituted C 1 to C 3 acyl, saturated or unsaturated substituted or unsubstituted C 1 to C 3 alkoxycarbonyl, NR C R D ;
优选地，取代基RC和RD各自独立地选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基、-S(O)nRE或NRFRG取代C1～C3烷基，被卤素、羟基、-S(O)nRE或NRFRG取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基、-S(O)nRE或NRFRG取代C1～C3烷氧基，被卤素、羟基、-S(O)nRE或NRFRG取代的C3～C6环烷氧基。Preferably, the substituents RC and RD are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or Unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl, -S(O) n R E or NR F R G , substituted by halogen, hydroxyl, -S(O) n R E or NR F R G C 3 ~ C 6 cycloalkyl, saturated or unsaturated C 1 ~ C 3 alkoxy, C 3 ~ C 6 cycloalkoxy, saturated or unsaturated by halogen, hydroxyl, -S(O) n R C 1 to C 3 alkoxy group substituted by E or NR F RG , C 3 to C 6 cycloalkoxy group substituted by halogen, hydroxyl, -S(O) n RE E or NR F RG .
优选地，RE、RF和RG各自独立地选自氢，氘，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基。Preferably, RE , RF and RG are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl , saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 to C 3 alkoxy Base, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 3 alkoxy group substituted by halogen, hydroxyl or amino group, C 3 to C 6 cycloalkoxy group substituted by halogen, hydroxyl group or amino group .
优选地，A7为C。Preferably, A 7 is C.
优选地，R1和R2各自独立地为氢、饱和或不饱和的取代或未取代的C1～C6烷基、饱和或不饱和的取代或未取代的C3～C6环烷基、-OC(＝O)C1-6烷基、-OC(＝O)C3～C6环烷基、-C(＝O)OC1-6烷基、-C(＝O)OC3～C6环烷基、饱和或不饱和的取代或未取代的C1～C6烷氧基、饱和或不饱和的取代或未取代的C3～C6环烷氧基、-S(O)nRc、NRCRD、饱和或不饱和的取代或未取代的C1～C6磺酰基、饱和或不饱和的取代或未取代的C1～C6酰基、C6～C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂芳基，其中所述“取代”是指选择性地含有1至4个选自羟基、卤素、氰基、磺酰基、氨基、-S(O)nRc、NRCRD、饱和或不饱和的C1～C6烷基、饱和或不饱和的C3～C6环烷基、-OC(＝O)C1-6烷基、-OC(＝O)C3～C6环烷基、-C(＝O)OC1-6烷基、-C(＝O)OC3～C6环烷基、饱和或不饱和的C1～C6磺酰基、饱和或不饱和的C1～C6酰基、C6～C10芳基、含有1至3个选自N、O和S的杂原子的6至10元杂环烷基或杂芳基的取代基；Preferably, R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 to C 6 alkyl, saturated or unsaturated substituted or unsubstituted C 3 to C 6 cycloalkyl , -OC(=O)C 1-6 alkyl, -OC(=O)C 3 to C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 ~C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 ~ C 6 alkoxy, saturated or unsaturated substituted or unsubstituted C 3 ~ C 6 cycloalkoxy, -S(O ) n Rc, NR CRD , saturated or unsaturated substituted or unsubstituted C 1 to C 6 sulfonyl group, saturated or unsaturated substituted or unsubstituted C 1 to C 6 acyl group, C 6 to C 10 aryl base, a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to optionally containing 1 to 4 selected from hydroxyl, halogen, cyano group , Sulfonyl group, amino group, -S(O) n Rc, NR CRD , saturated or unsaturated C 1 to C 6 alkyl group, saturated or unsaturated C 3 to C 6 cycloalkyl group, -OC(＝ O)C 1-6 alkyl, -OC(=O)C 3 to C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 to C 6 cycloalkyl base, saturated or unsaturated C 1 to C 6 sulfonyl group, saturated or unsaturated C 1 to C 6 acyl group, C 6 to C 10 aryl group, containing 1 to 3 heteroatoms selected from N, O and S 6 to 10 membered heterocycloalkyl or heteroaryl substituents;
或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的4至10元杂环烷基，取代或未取代的含有1至3个选自N、O和S的杂原子的5至10元杂芳基，其中所述“取代”是指选择性地含有1至4个选自羟基，卤素，氰基，磺酰基，氨基，-S(O)nRc，NRCRD，C1～C6烷基，C3～C6环烷基，C1～C6烷氧基，C3～C6环烷氧基，-OC(＝O)C1-6烷基，-OC(＝O)C3～C6环烷基，-C(＝O)OC1-6烷基，-C(＝O)OC3～C6环烷基，被卤素、羟基、氨基或RE取代C1～C6烷基、C3～C6环烷基、C1～C6烷氧基、C3～C6环烷氧基的取代基，其中RE选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C6烷基，C3～C6环烷基，-S(O)nRc，NRCRD，饱和或不饱和的被氘、卤素、羟基或氨基取代C1～C6烷基，被氘、卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C6烷氧基，C3～C6环烷氧基，饱和或不饱和的被氘、卤素、羟基或氨基取代C1～C6烷氧基，被氘、卤素、羟基或氨基取代的C3～C6环烷氧基；Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 4 to 10 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 10 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl , amino, -S(O) n Rc, NR C R D , C 1 ~ C 6 alkyl, C 3 ~ C 6 cycloalkyl, C 1 ~ C 6 alkoxy, C 3 ~ C 6 cycloalkoxy Base, -OC(=O)C 1-6 alkyl, -OC(=O)C 3 ~ C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 to C 6 cycloalkyl, substituted by halogen, hydroxyl, amino or RE C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkoxy, C 3 to C 6 ring Substituent of alkoxy group, wherein RE is selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, -S(O) n Rc, NR CRD , saturated or unsaturated C 1 to C 6 alkyl substituted by deuterium, halogen , hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by deuterium, halogen, hydroxyl or amino, saturated Or unsaturated C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 6 alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by deuterium, halogen , hydroxyl- or amino-substituted C 3 ~ C 6 cycloalkoxy group;
优选地，R3为卤素、-S(O)nRc，NRCRD，饱和或不饱和的C1～C6烷基、C3～C6环烷基，C1～C6烷氧基、C3～C6环烷氧基；饱和或不饱和的被卤素、羟基、氨基或RH取代的C1～C6烷基、C3～C6环烷基、C1～C6烷氧基、C3～C6环烷氧基，其中取代基RH选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基。Preferably, R 3 is halogen, -S(O) n Rc, NR C RD , saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group; saturated or unsaturated C 1 to C 6 alkyl group, C 3 to C 6 cycloalkyl group, C 1 to C 6 substituted by halogen, hydroxyl, amino or R H Alkoxy, C 3 to C 6 cycloalkoxy, wherein the substituent R H is selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 Cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 to C 3 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 3 alkoxy group, substituted by halogen, hydroxyl or amino group, C 3 to C 6 ring substituted by halogen, hydroxyl group or amino group Alkoxy.
更优选地，R1和R2各自独立地为氢、饱和或不饱和的取代或未取代的C1～C3烷基、 饱和或不饱和的取代或未取代的C3～C6环烷基、-OC(＝O)C1-3烷基、-OC(＝O)C3～C6环烷基、-C(＝O)OC1-3烷基、-C(＝O)OC3～C6环烷基、-S(O)nRc、NRCRD、饱和或不饱和的取代或未取代的C1～C3磺酰基、饱和或不饱和的取代或未取代的C1～C3酰基，C6～C10芳基、含有1至3个选自N、O和S的杂原子的6至8元杂芳基，其中所述“取代”是指选择性地含有1至4个选自羟基、卤素、氰基、磺酰基、氨基、-S(O)nRc、NRCRD、-OC(＝O)C1-3烷基、-OC(＝O)C3～C6环烷基、-C(＝O)OC1-3烷基、-C(＝O)OC3～C6环烷基、饱和或不饱和的C1～C3烷基、饱和或不饱和的C3～C6环烷基、饱和或不饱和的C1～C3磺酰基、饱和或不饱和的C1～C3酰基、C6～C10芳基、含有1至3个选自N、O和S的杂原子的6至8元杂芳基的取代基；More preferably, R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 to C 3 alkyl, Saturated or unsaturated substituted or unsubstituted C 3 to C 6 cycloalkyl, -OC(=O)C 1-3 alkyl, -OC(=O)C 3 to C 6 cycloalkyl, -C( =O)OC 1-3 alkyl, -C(=O)OC 3 to C 6 cycloalkyl, -S(O) n Rc, NR C R D , saturated or unsaturated substituted or unsubstituted C 1 ~C 3 sulfonyl group, saturated or unsaturated substituted or unsubstituted C 1 ~ C 3 acyl group, C 6 ~ C 10 aryl group, 6 to 8 containing 1 to 3 heteroatoms selected from N, O and S Metaheteroaryl, wherein the "substituted" refers to optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl, amino, -S(O) n Rc, NR C RD , -OC (=O)C 1-3 alkyl, -OC(=O)C 3 to C 6 cycloalkyl, -C(=O)OC 1-3 alkyl, -C(=O)OC 3 to C 6 Cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl, saturated or unsaturated C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 sulfonyl, saturated or unsaturated C Substituents of 1 to 3 acyl groups, C 6 to 10 aryl groups, and 6 to 8-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S;
或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的5至10元杂环烷基，取代或未取代的含有1至3个选自N、O和S的杂原子的5至10元杂芳基，其中所述“取代”是指选择性地含有1至4个选自羟基、卤素、氰基、磺酰基、氨基、-S(O)nRc、NRCRD、C1～C3烷基、C3～C6环烷基C1～C3烷氧基、C3～C6环烷氧基，-OC(＝O)C1-3烷基，-OC(＝O)C3～C6环烷基，-C(＝O)OC1-3烷基，-C(＝O)OC3～C6环烷基，被卤素、羟基、氨基或RH取代C1～C3烷基、C3～C6环烷基、C1～C3烷氧基、C3～C6环烷氧基的取代基，其中RH选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基，C3～C6环烷基，-S(O)nRc，NRCRD，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基；Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 10 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl , amino, -S(O) n Rc, NR CRD , C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 3 alkoxy , C 3 to C 6 cycloalkoxy , -OC(=O)C 1-3 alkyl, -OC(=O)C 3 ~ C 6 cycloalkyl, -C(=O)OC 1-3 alkyl, -C(=O)OC 3 ~C 6 cycloalkyl, substituted by halogen, hydroxyl, amino or R H C 1 ~ C 3 alkyl, C 3 ~ C 6 cycloalkyl, C 1 ~ C 3 alkoxy, C 3 ~ C 6 cycloalkyl The substituent of the oxygen group, where R H is selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, -S(O) n Rc, NR CRD , saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl or amino , C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 ～C 3 alkoxy group, C 3 ～C 6 cycloalkoxy group, saturated or unsaturated C 1 ～C 3 alkoxy group, substituted by halogen, hydroxyl or amino group, C 3 ～ C 6 cycloalkoxy;
更优选地，R3为卤素、-S(O)nRc，NRCRD，饱和或不饱和的C1～C3烷基、C3～C6环烷基，C1～C3烷氧基、C3～C6环烷氧基；饱和或不饱和的被卤素、羟基、氨基或RF取代的C1～C3烷基、C3～C6环烷基、C1～C3烷氧基、C3～C6环烷氧基，其中取代基RH选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基。More preferably, R 3 is halogen, -S(O) n Rc, NR C RD , saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 3 alkyl Oxygen group, C 3 ~ C 6 cycloalkoxy group; saturated or unsaturated C 1 ~ C 3 alkyl group, C 3 ~ C 6 cycloalkyl group, C 1 ~ C substituted by halogen, hydroxyl, amino or RF 3 alkoxy, C 3 ~ C 6 cycloalkoxy, wherein the substituent R H is selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 ~ C 3 alkyl, C 3 ~ C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 to C 3 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 3 alkoxy group, substituted by halogen, hydroxyl or amino group, C 3 to C 6 substituted by halogen, hydroxyl group or amino group Cycloalkoxy.
更优选的，R1和R2与连接它们的N原子一起形成的结构选自以下基团中：

More preferably, the structure formed by R 1 and R 2 together with the N atom connecting them is selected from the following groups:

更优选地，根据本发明的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐选自以下化合物中：




More preferably, according to the substituted pyrimidine hydrazides of the present invention, each of its optical isomers, prodrugs or pharmaceutically acceptable salts is selected from the following compounds:




根据本发明的第二个方面，本发明的另一目的在于提供一种药物组合物，所述药物组合物包含治疗有效量的根据本发明的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐和药学上可接受的赋形剂或载体。According to a second aspect of the present invention, another object of the present invention is to provide a pharmaceutical composition, said pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrimidine hydrazide compound according to the present invention, each of which is an optical isomer. , a prodrug or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or carrier.
根据本发明的第三个方面，本发明的另一目的在于提供根据本发明的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐在制备AHR紊乱抑制剂中的用途。According to the third aspect of the present invention, another object of the present invention is to provide substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts for the preparation of AHR disorder inhibitors use in.
根据本发明的第四个方面，本发明的另一目的在于提供根据本发明的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐在制备治疗与AHR紊乱相关的肿瘤的药物中的应用。According to the fourth aspect of the present invention, another object of the present invention is to provide substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts for the preparation of treatments for AHR disorders. Applications related to oncology drugs.
根据本发明的第五个方面，本发明的另一目的在于提供一种治疗与AHR紊乱相关的肿瘤的方法，所述方法包括向需要其的受试者施用有效量的根据本发明的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐或根据本发明的所述药物组合物。According to a fifth aspect of the invention, another object of the invention is to provide a method for treating tumors associated with AHR disorders, the method comprising administering an effective amount of a substituted pyrimidine according to the invention to a subject in need thereof Hydrazide compounds, their respective optical isomers, prodrugs or pharmaceutically acceptable salts or the pharmaceutical composition according to the present invention.
根据本发明的第六个方面，本发明的另一目的在于提供根据本发明的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐的制备方法，所述方法如下反应式1所示：
According to the sixth aspect of the present invention, another object of the present invention is to provide a method for preparing the substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts, The method is as shown in reaction equation 1 below:
式III表示的羧酸化合物与式ⅠV表示的肼化合物进行缩合反应得到式Ⅰ所示的取代嘧啶酰肼类化合物；The carboxylic acid compound represented by formula III and the hydrazine compound represented by formula IV are subjected to a condensation reaction to obtain a substituted pyrimidine hydrazide compound represented by formula I;
其中式III表示的羧酸化合物按照如下方法之一制备：The carboxylic acid compound represented by formula III is prepared according to one of the following methods:
方法A
Method A
1)式V表示的甲基羰基化合物与草酸二甲酯反应得到式VI表示的化合物；1) The methyl carbonyl compound represented by formula V reacts with dimethyl oxalate to obtain the compound represented by formula VI;
2)式VI表示的化合物与式X表示的肼化合物进行成环反应得到式VIⅠ表示的嘧啶化合物；2) The compound represented by formula VI and the hydrazine compound represented by formula X undergo a ring-forming reaction to obtain a pyrimidine compound represented by formula VII;
3)式VIⅠ表示的嘧啶化合物经过水解反应得到式III表示的羧酸化合物； 3) The pyrimidine compound represented by formula VII is subjected to a hydrolysis reaction to obtain the carboxylic acid compound represented by formula III;
方法B
Method B
1)式V表示的甲基羰基化合物与草酸单烷基酯反应得到式VIIⅠ表示的化合物，其中取代基R为甲基、乙基、异丙基、特丁基等；1) Methyl carbonyl compound represented by formula V and monoalkyl oxalate The reaction yields a compound represented by formula VIII, in which the substituent R is methyl, ethyl, isopropyl, tert-butyl, etc.;
2)式VIIⅠ表示的化合物与式X表示的肼化合物进行成环反应得到式IX表示的嘧啶化合物；2) The compound represented by formula VIII and the hydrazine compound represented by formula X undergo a ring-forming reaction to obtain a pyrimidine compound represented by formula IX;
3)式IX表示的嘧啶化合物经过水解反应脱除取代基R得到式III表示的羧酸化合物；3) The pyrimidine compound represented by Formula IX undergoes a hydrolysis reaction to remove the substituent R to obtain the carboxylic acid compound represented by Formula III;
方法C
Method C
1)式V表示的甲基羰基化合物与尿素进行成环反应，得到式XI表示的化合物；1) The methyl carbonyl compound represented by formula V undergoes a cyclization reaction with urea to obtain the compound represented by formula XI;
2)式XI表示的化合物与氯化试剂反应，如三氯氧磷、五氯化磷、氯化亚砜等，得到式XII表示的氯代化合物；2) The compound represented by formula XI reacts with a chlorinating reagent, such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, etc., to obtain the chlorinated compound represented by formula XII;
3)式XII表示的氯代化合物与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，生成式XIII表示的化合物；3) Chlorinated compounds and boric acid compounds represented by formula XII Or react with the corresponding borate ester or trialkyl tin compound to generate the compound represented by formula XIII;
4)式XIII表示的化合物脱去乙基形成羧酸基，得到式III表示的化合物；4) The compound represented by formula XIII removes the ethyl group to form a carboxylic acid group to obtain the compound represented by formula III;
方法D
Method D
1)碳酸酯化合物与式X表示的肼化合物发生成环反应，得到式XIV表示的化合物；1) Carbonate compounds A cyclization reaction occurs with the hydrazine compound represented by formula X to obtain a compound represented by formula XIV;
2)式XIV表示的化合物与氯化试剂反应，如三氯氧磷、五氯化磷、氯化亚砜等，得到式XV表示的氯代化合物；2) The compound represented by formula XIV reacts with a chlorinating reagent, such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, etc., to obtain a chlorinated compound represented by formula XV;
3)式XV表示的氯代化合物与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，得到式III表示的化合物；3) Chlorinated compounds and boric acid compounds represented by formula XV Or react with the corresponding borate ester or trialkyl tin compound to obtain the compound represented by formula III;
方法E
Method E
1)嘧啶化合物与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，分离纯化后得到化合物 1) Pyrimidine compounds with boric acid compounds Or react with the corresponding borate ester or trialkyl tin compound, and obtain the compound after separation and purification
2)化合物再与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，得到式III表示的化合物；2) Compounds Boric acid compound Or react with the corresponding borate ester or trialkyl tin compound to obtain the compound represented by formula III;
方法F
Method F
1)嘧啶化合物与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，分离纯化后得到式XV表示的化合物；1) Pyrimidine compounds with boric acid compounds Or react with the corresponding borate ester or trialkyl tin compound, and obtain the compound represented by formula XV after separation and purification;
2)式XV表示的化合物再与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，得到式III表示的化合物。2) The compound represented by formula XV is then mixed with a boric acid compound Or react with the corresponding borate ester or trialkyl tin compound to obtain the compound represented by formula III.
本发明中式IV表示的肼化合物的合成流程如下所示：The synthesis process of the hydrazine compound represented by formula IV of the present invention is as follows:
方法G
Method G
1)将BocNHNH2(叔丁氧羰基肼)溶解在如甲醇、乙醇等醇类溶剂中，然后加入酮类化合物(R1(C＝O)R1)或醛类化合物(R1(C＝O)H)反应，然后加入硼氢化钠加氢还原，纯化分离得到化合物 1) Dissolve BocNHNH 2 (tert-butoxycarbonyl hydrazine) in alcoholic solvents such as methanol, ethanol, etc., and then add ketone compounds (R 1 (C＝O)R 1 ) or aldehyde compounds (R 1 (C＝ O)H) reaction, then add sodium borohydride for hydrogenation reduction, and purify and isolate the compound.
2)将化合物溶解在如N,N-二异丙基乙胺(DIEA)等胺类溶剂中，然后加入酮类化合物(R2(C＝O)R2)、醛类化合物(R2(C＝O)H)或相应的R2取代的环氧化合物进行反应，得到化合物 2) Combine the compound Dissolve in an amine solvent such as N,N-diisopropylethylamine (DIEA), then add ketone compounds (R 2 (C＝O)R 2 ) and aldehyde compounds (R 2 (C＝O) H) or the corresponding R 2 substituted epoxy compound reacts to obtain the compound
3)将化合物溶解在如甲醇、乙醇等醇类溶剂中，然后加入过量的HCl的甲醇溶液，得到式IV表示的化合物的盐酸盐； 3) Combine the compound Dissolve in alcoholic solvents such as methanol and ethanol, and then add excess HCl methanol solution to obtain the hydrochloride of the compound represented by formula IV;
方法H
Method H
1)将取代的氨基化合物(HNR1R2)溶解在溶剂中，加入亚硝化试剂，所述亚硝化试剂选自亚硝酸叔丁酯、亚硝酸异丁酯，加热回流，减压浓缩得到中间体亚硝胺基化合物(R1N(R2)-N＝O)；1) Dissolve the substituted amino compound (HNR 1 R 2 ) in a solvent, add a nitrosating reagent selected from tert-butyl nitrite and isobutyl nitrite, heat to reflux, and concentrate under reduced pressure to obtain the intermediate Nitrosamine-based compound (R 1 N(R 2 )-N=O);
2)将亚硝胺基化合物(R1N(R2)-N＝O)溶解在溶剂中，加入如氢化铝锂的氢化试剂进行加氢反应，得到式IV表示的化合物。2) Dissolve the nitrosamine-based compound (R 1 N (R 2 )-N=O) in a solvent, add a hydrogenation reagent such as lithium aluminum hydride to perform a hydrogenation reaction, and obtain the compound represented by Formula IV.
具体实施方式Detailed ways
以下，将详细地描述本发明。在进行描述之前，应当理解的是，在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义，而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上，根据与本发明的技术方面相应的含义和概念进行解释。因此，这里提出的描述仅仅是出于举例说明目的的优选实例，并非意图限制本发明的范围，从而应当理解的是，在不偏离本发明的精神和范围的情况下，可以由其获得其他等价方式或改进方式。Hereinafter, the present invention will be described in detail. Before proceeding to the description, it is to be understood that the terms used in this specification and the appended claims should not be construed to be limited to ordinary and dictionary meanings, but rather to allow the inventor to appropriately define the terms for best interpretation. On the basis of the principles, explanations are made according to the meanings and concepts corresponding to the technical aspects of the present invention. Accordingly, the descriptions set forth herein are preferred examples for illustrative purposes only and are not intended to limit the scope of the invention, so that it will be understood that others may be derived therefrom without departing from the spirit and scope of the invention. price or improvement methods.
当列出一系列值时，意图涵盖该范围内的每个值和子范围。例如，“C1至C8”意图涵盖C1、C2、C3、C4、C5、C6、C7、C8、C1–8、C1–7、C1–6、C1–5、C1–4、C1–3、C1–2、C2-8、C2-7、C2–6、C2–5、C2–4、C2–3、C3-8、C3-7、C3–6、C3–5、C3–4、C4-8、C4-7、C4–6、C4–5、C5-8、C5-7、C5–6、C6-8、C6-7和C7-8。When a range of values is listed, the intention is to cover every value and subrange within the range. For example, "C 1 to C 8 " is intended to cover C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 1–8 , C 1–7 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2-8 , C 2-7 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3-8 , C 3-7 , C 3–6 , C 3–5 , C 3–4 , C 4-8 , C 4-7 , C 4–6 , C 4–5 , C 5-8 , C 5-7 , C 5–6 , C 6-8 , C 6-7 and C 7-8 .
定义definition
“烷基”是指具有1至8个碳原子的直链或支链饱和烃基的基团(“C1–8烷基”)。在一些实施方案中，烷基具有1至7个碳原子(“C1-7烷基”)。在一些实施方案中，烷基具有1至6个碳原子(“C1-6烷基”)。在一些实施方案中，烷基具有1至5个碳原子(“C1-5烷基”)。在一些实施方案中，烷基具有1至4个碳原子(“C1-4烷基”)。在一些实施方案中，烷基具有1至3个碳原子(“C1-3烷基”)。在一些实施方案中，烷基具有1至2个碳原子(“C1-2烷基”)。在一些实施方案中，烷基具有1个碳原子(“C1烷基”)。在一些实施方案中，烷基具有1至6个碳原子(“C1-6烷基”)。C1–6烷基的实例包括甲基(C1)，乙基(C2)，丙基(C3)(例如，正丙基、异丙基)，丁基(C4)(例如正丁基、叔丁基、仲丁基、异丁基)，戊基(C5)(例如，正戊基、3-戊基、新戊基、3-甲基-2-丁基、叔戊基)和己基(C6)(例如，正己基)。烷基的另外的实例包括正庚基(C7)、正辛基(C8)等。除非另有说明，烷基的每个实例独立地未被取代(“未取代的烷基”)或被一个或多个取代基(例如，卤素，如F)所取代(“取代的烷基”)。在某些实施方案中，烷基是未取代的C1-8烷基(例如未取代的C1烷基，如-CH3)。在某些实施方案中，烷基为取代的C1-8烷基(例如取代的C1烷基，如-CF3)。"Alkyl" refers to a straight or branched chain saturated hydrocarbon radical having 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C 1 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl"). Examples of C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-propyl) Butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C 5 ) (for example, n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl group) and hexyl (C 6 ) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) ("substituted alkyl" ). In certain embodiments, alkyl is unsubstituted C 1-8 alkyl (eg, unsubstituted C 1 alkyl, such as -CH 3 ). In certain embodiments, alkyl is substituted C 1-8 alkyl (eg, substituted C 1 alkyl, such as -CF 3 ).
“烷氧基”表示单价O烷基，其中所述烷基部分具有指定数目的碳原子。本公开中烷氧基通常含有1 6个碳原子(“C1至C6烷氧基”)，或1 4个碳原子(“C1C4烷氧基”)。例如，C1C4烷氧基包括甲氧基、乙氧基、异丙氧基、叔丁基氧基等。除非另有说明，烷氧基的每个实例独立地任选被取代，即未取代(“未取代的烷氧基”)或被一个或多个取代基所取代(“取代的烷氧基”)。在某些实施方案中，烷氧基是未取代的C1至C6烷氧基。在某些实施方案中，烷氧基是取代的C1至C6烷氧基。"Alkoxy" means a monovalent O alkyl group, wherein the alkyl moiety has the specified number of carbon atoms. In this disclosure, alkoxy groups typically contain 16 carbon atoms ("C1 to C6 alkoxy"), or 14 carbon atoms ("C1C4 alkoxy"). For example, C1C4 alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy, etc. Unless otherwise specified, each instance of alkoxy is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkoxy") or substituted with one or more substituents ("substituted alkoxy" ). In certain embodiments, alkoxy is unsubstituted C1 to C6 alkoxy. In certain embodiments, alkoxy is substituted C1 to C6 alkoxy.
“环烷基”是指非芳族环系中具有3至8个环碳原子(“C3-8环烷基”)和零个杂原子的非芳族环烃基的基团。在一些实施方案中，环烷基团具有3至8个环碳原子(“C3-8环烷 基”)。在一些实施方案中，环烷基团具有3至6个环碳原子(“C3-6环烷基”)。在一些实施方案中，环烷基具有5至8个环碳原子(“C5-8环烷基”)。示例性的C3-6环烷基团包括但不限于环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环己二烯基(C6)等。示例性的C3-8环烷基团包括但不限于上述C3-6环烷基团以及环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7)、环辛基(C8)、环辛烯基(C8)等。除非另有说明，环烷基的每个实例独立地任选被取代，即未取代(“未取代的环烷基”)或被一个或多个取代基所取代(“取代的环烷基”)。在某些实施方案中，环烷基是未取代的C3-8环烷基；在某些实施方案中，环烷基是取代的C3-8环烷基。"Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl") and zero heteroatoms in a non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl group"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 8 ring carbon atoms atom ("C 5-8 cycloalkyl"). Exemplary C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentenyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl ( C 6 ), etc. Exemplary C 3-8 cycloalkyl groups include, but are not limited to, the above-mentioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptyldi Alkenyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), etc. Unless otherwise stated, each example of cycloalkyl is independently any is optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, cycloalkyl is unsubstituted C 3-8 cycloalkyl; in certain embodiments, cycloalkyl is substituted C 3-8 cycloalkyl.
“杂环烷基”是指具有环碳原子和1至4个环杂原子的5至14元非芳族环系的基团，其中每个杂原子独立地选自氮、氧和硫(“5-14元杂环基团”)。在含有一个或多个氮原子的杂环基团中，只要化合价所允许，连接点可以是碳原子或氮原子。杂环基团可以是单环(“单环杂环基团”)或稠环、桥环或螺环系，例如双环系(“双环杂环基”)，并且可以是饱和的或可以是部分不饱和的。“杂环基团”还包括其中如上所定义的杂环与一个或多个环烷基基团稠合(其中连接点在环烷基团或杂环上)的环系，或其中如上所定义的杂环与一个或多个芳基或杂芳基基团稠合(其中连接点在杂环上)的环系，并且在这种情况下，环成员的数目继续指代杂环系中环成员的数目。除非另有说明，杂环基团的每个实例独立地任选地被取代，即未取代(“未取代的杂环烷基”)或被一个或多个取代基所取代(“取代的杂环烷基”)。在某些实施方案中，杂环烷基是未取代的5-14元杂环烷基。在某些实施方案中，杂环烷基取代的5-14元杂环烷基。"Heterocycloalkyl" means a group of 5 to 14 membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (" 5-14 membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, as long as the valency permits. Heterocyclic groups may be monocyclic ("monocyclic heterocyclyl") or fused, bridged or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or may be partially Unsaturated. "Heterocyclyl group" also includes ring systems in which a heterocycle as defined above is fused to one or more cycloalkyl groups (where the point of attachment is on the cycloalkyl group or heterocycle), or in which a heterocycle as defined above is fused A ring system in which a heterocycle is fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocycle), and in this case the number of ring members continues to refer to the ring members in the heterocycle system Number of. Unless otherwise specified, each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted with one or more substituents ("substituted heterocycloalkyl"). Cycloalkyl"). In certain embodiments, heterocycloalkyl is unsubstituted 5-14 membered heterocycloalkyl. In certain embodiments, heterocycloalkyl substituted 5-14 membered heterocycloalkyl.
“芳基”或“芳香环”或“芳香环基”是指具有在芳环系中提供的6-14个环碳原子和零个杂原子的单环或多环(例如，二环或三环)4n+2芳族环系(例如，具有在环状阵列中共享的6、10或14个π电子)的基团(“C6-14芳基”)。在一些实施方案中，芳基具有6个环碳原子(“C6芳基”；例如，苯基)。在一些实施方案中，芳基具有10个环碳原子(“C10芳基”；例如，萘基，如1-萘基和2-萘基)。在一些实施方案中，芳基具有14个环碳原子(“C14芳基”；例如，蒽基)。“芳基”还包括其中如上定义的芳基环与一个或多个环烷基或杂环基团稠合(其中连接点在芳环上)的环系，并且在这种情况下，碳原子的数目继续以指代芳环系中的碳原子数目。除非另有说明，芳基的每个实例独立地任选被取代，即未取代(“未取代的芳基”)或被一个或多个取代基所取代(“取代的芳基”)。在某些实施方案中，芳基是未取代的C6-14芳基。在某些实施方案中，芳基是取代的C6-14芳基。"Aryl" or "aromatic ring" or "aromatic ring group" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic ring) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. Ring) A group of 4n+2 aromatic ring systems (eg, having 6, 10, or 14 π electrons shared in a cyclic array) ("C 6-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C 6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 aryl"; for example, anthracenyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the aromatic ring, and in this case, the carbon atom The number continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise specified, each instance of aryl is independently optionally substituted, ie, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, aryl is unsubstituted C 6-14 aryl. In certain embodiments, aryl is substituted C 6-14 aryl.
“杂芳基”是具有在芳族环系中提供的环碳原子和1-4个环杂原子的5-14元芳族环系，其中每个杂原子独立地选自氮、氧和硫(“5-14元杂芳基”)。在一些实施方案中，杂芳基是具有在芳族环系中提供的环碳原子和1-4个环杂原子的5-8元芳族环系，其中每个杂原子独立地选自氮、氧和硫(“5-8元杂芳基”)。在一些实施方案中，杂芳基是具有在芳族环系中提供的环碳原子和1-4个环杂原子的5-6元芳族环系，其中每个杂原子独立地选自氮、氧和硫(“5-6元杂芳基”)。在一些实施方案中，5-6元杂芳基具有1-3个选自氮、氧和硫的环杂原子。在一些实施方案中，5-6元杂芳基具有1-2个选自氮、氧和硫的环杂原子。在一些实施方案中，5-6元杂芳基具有1个选自氮、氧和硫的环杂原子。除非另有说明，杂芳基的每个实例独立地任选被取代，即未取代(“未取代的杂芳基”)或被一个或多个取代基所取代(“取代的杂芳基”)。在某些实施方案中，杂芳基是未取代的5-14元杂芳基。在某些实施方案中，杂芳基是取代的5-14元杂芳基。"Heteroaryl" is a 5-14 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl"). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl" ). In certain embodiments, heteroaryl is unsubstituted 5-14 membered heteroaryl. In certain embodiments, heteroaryl is substituted 5-14 membered heteroaryl.
“卤素”或“卤代”是指氟(氟，-F)、氯(氯，-Cl)、溴(溴，-Br)或碘(碘，-I)。"Halogen" or "halo" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).
“取代的”或“任选取代的”是指基团中的原子，例如氢原子被取代。在某些实施方案中，烷基、环烷基、杂环基、芳基和杂芳基被取代(例如“取代的”烷基、“取代的”环烷基、“取代的”杂环烷基、“取代的”芳基，或“取代的”杂芳基)。通常，术语“取代的”，无论之前是 否有术语“任选地”，意指存在于基团(例如，碳或氮原子)上的至少一个氢被可允许的取代基取代，例如，取代基在取代后会形成稳定的化合物，例如，不会(如通过重排、环化、消除或其他反应)自发地发生转化的化合物。除非另外指明，否则“取代的”基团在该基团的一个或多个可取代的位置上具有取代基，并且当任何给定结构中的多于一个位置被取代时，取代基在每个位置处相同或不同。预期术语“取代的”包括用有机化合物的所有可允许的取代基、任何导致形成稳定化合物的本文所述的取代基所取代。本公开预期任何和所有这些组合以获得稳定的化合物。为了本公开的目的，如氮的杂原子可以具有氢取代基和/或如本文所述的满足杂原子的化合价并导致形成稳定的部分的任何合适的取代基。在某些实施方案中，取代基是碳原子取代基。在某些实施方案中，取代基是氮原子取代基。在某些实施方案中，取代基是氧原子取代基。在某些实施方案中，取代基是硫原子取代基。"Substituted" or "optionally substituted" means that an atom, such as a hydrogen atom, in the group is substituted. In certain embodiments, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted (e.g., "substituted" alkyl, "substituted" cycloalkyl, "substituted" heterocycloalkyl radical, "substituted" aryl, or "substituted" heteroaryl). Usually, the term "superseded", whatever is preceded by Where the term "optionally" is present, it is meant that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is substituted by a permissible substituent, e.g., the substituent will form a stable compound when substituted, e.g. , compounds that do not undergo spontaneous transformation (eg, by rearrangement, cyclization, elimination, or other reactions). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions on the group, and when more than one position in any given structure is substituted, the substituent is present at each The location is the same or different. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituent described herein that results in the formation of a stable compound. This disclosure contemplates any and all of these combinations to obtain stable compounds. For purposes of this disclosure, a heteroatom such as nitrogen may have a hydrogen substituent and/or any suitable substituent as described herein that satisfies the valency of the heteroatom and results in the formation of a stable moiety. In certain embodiments, the substituents are carbon atom substituents. In certain embodiments, the substituents are nitrogen atom substituents. In certain embodiments, the substituents are oxygen atom substituents. In certain embodiments, the substituent is a sulfur atom substituent.
“不饱和的”或“部分不饱和的”是指包含至少一个双键或三键的基团。“部分不饱和的”环系还旨在涵盖具有多个不饱和位点的环，但不旨在包括芳香族基团(例如，芳基或杂芳基)。同样，“饱和”是指不含双键或三键的基团，即全部含单键。"Unsaturated" or "partially unsaturated" refers to a group containing at least one double or triple bond. "Partially unsaturated" ring systems are also intended to encompass rings having multiple sites of unsaturation, but are not intended to include aromatic groups (eg, aryl or heteroaryl). Likewise, "saturated" refers to a group that contains no double or triple bonds, that is, all single bonds.
本文中，当定义的取代基中存在多重取代时，这种多重取代的文字描述中可能存在重复定义的情况，但这种描述应理解为至少符合一般药物化学的基本规律，例如当取代基出现重复定义时，本领域技术人员可以按照一般药物化学常识确定这种重复是可行的或不可行的。以取代基RA的定义为例，RA可以为“饱和或不饱和的C1～C8烷基”或“饱和或不饱和的被卤素、羟基、氨基或RC取代的C1～C8烷基”，且取代基Rc的定义中可以为“氢，卤素，羟基，氨基”等，本领域技术人员可以根据一般药物化学常识确定这种重复是否可行，并作出合理的选择。In this article, when there are multiple substitutions in a defined substituent, there may be repeated definitions in the text description of such multiple substitutions, but this description should be understood as at least consistent with the basic laws of general medicinal chemistry. For example, when a substituent appears When repeating a definition, those skilled in the art can determine whether such repeating is feasible or unfeasible based on common common sense in medicinal chemistry. Taking the definition of substituent RA as an example, RA can be "saturated or unsaturated C 1 to C 8 alkyl" or "saturated or unsaturated C 1 to C substituted by halogen, hydroxyl, amino or R C 8 alkyl", and the substituent Rc can be defined as "hydrogen, halogen, hydroxyl, amino", etc. Those skilled in the art can determine whether such repetition is feasible based on general medicinal chemistry knowledge and make a reasonable choice.
本文中采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐(即药学上可接受的盐)，实例包括无机酸盐以及有机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；所述有机酸包括如苯甲酸、2-羟基乙磺酸、氨基磺酸、苯磺酸、苯乙酸、扁桃酸、丙二酸、丙酸、草酸、对氨基苯磺酸、对甲苯磺酸、多聚半乳糖醛酸、泛酸、富马酸、谷氨酸、琥珀酸、甲烷磺酸、酒石酸、抗坏血酸、邻苯二甲酸、马来酸、柠檬酸、苹果酸、葡庚糖酸、葡糖酸、羟乙磺酸、乳酸、乳糖酸、十二烷基磺酸、双羟萘酸、水杨酸、辛二酸、亚叶酸、依地酸、乙醇酸、乙酸、乙烷磺酸、异丁酸、硬脂酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutical Acceptable salts above), examples include inorganic acid salts and organic acid salts, the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid , hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; the organic acids include benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, Oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methane sulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, Citric acid, malic acid, glucoheptonic acid, gluconic acid, isethionic acid, lactic acid, lactobionic acid, dodecyl sulfonic acid, pamoic acid, salicylic acid, suberic acid, leucovorin, edetate Acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid and similar acids; also includes salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
如本文所用，修饰词术语“约”是指可能发生的数值变化，例如，通过常规测试和处理；通过此类测试和处理中的无意错误；通过本发明所用成分的制造，来源或纯度上的差异；等等。如本文所用，“约”特定值还包括该特定值，例如，约10％包括10％。不论是否被术语“约”修饰，权利要求均包括所列举数量的等同形式。在一个实施方式中，术语“约” 是指在所报告的数值的20％以内。As used herein, the modifier term "about" refers to numerical variations that may occur, e.g., through routine testing and handling; through inadvertent errors in such testing and handling; through variations in the manufacture, source, or purity of the ingredients used in the invention. Difference; etc. As used herein, "about" a particular value also includes that particular value, for example, about 10% includes 10%. Whether or not modified by the term "about," the claims include equivalents of the recited quantities. In one embodiment, the term "about" means within 20% of the reported value.
如本文所用，术语“治疗”是指消除，减轻或改善疾病或病症和/或与其相关的症状。尽管没有排除，但是治疗疾病或病症并不需要完全消除与其相关的疾病，病症或症状。如本文所用，术语“治疗”等可以包括“预防性治疗”，是指在没有或有患上或易患疾病或病症或疾病或病症复发的风险的受试者中，降低疾病或病症的再发展或先前控制的疾病或病症的复发的可能性。术语“治疗”和同义词考虑向需要这种治疗的受试者施用治疗有效量的本文所述的化合物。As used herein, the term "treating" means eliminating, alleviating or ameliorating a disease or condition and/or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition or symptoms associated with it. As used herein, the term "treatment" and the like may include "preventive treatment" which refers to reducing the recurrence of a disease or condition in a subject who does not have or is at risk of developing or susceptible to the disease or condition or the recurrence of the disease or condition. The possibility of development or recurrence of a previously controlled disease or condition. The term "treatment" and synonyms contemplate the administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect. For the oral dosage form of the present invention, the "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
根据本发明的所述AHR紊乱相关的疾病包括但不限于肿瘤。Diseases related to the AHR disorder according to the present invention include, but are not limited to, tumors.
以下实施例仅是作为本发明的实施方案的例子列举，并不对本发明构成任何限制，本领域技术人员可以理解在不偏离本发明的实质和构思的范围内的修改均落入本发明的保护范围。除非特别说明，以下实施例中使用的试剂和仪器均为市售可得产品。The following examples are merely examples of embodiments of the present invention and do not constitute any limitation to the present invention. Those skilled in the art can understand that modifications within the scope that do not deviate from the essence and concept of the present invention fall within the protection of the present invention. scope. Unless otherwise stated, the reagents and instruments used in the following examples are all commercially available products.
实验部分：Experimental part:
实施例1：中间体III-A的制备，按照制备方法A
Example 1: Preparation of intermediate III-A according to preparation method A
步骤1)化合物VII-A的制备Step 1) Preparation of compound VII-A
将草酸二乙酯(15.2g，104mmol)的无水乙醇(250ml)和乙醇钠(10.9g，160mmol)混合溶液冷却至10度以下，搅拌30min，滴加三氟甲基苯甲酮(18.8g，100mmol)的无水乙醇溶液(80ml)，撤去冰浴，室温搅拌过夜，过滤，少量乙醇洗涤，干燥，得化合物VII-A(28g，收率97％)。LC/MS(ESI):m/z 289[M+1]+。Cool the mixed solution of diethyl oxalate (15.2g, 104mmol) in absolute ethanol (250ml) and sodium ethoxide (10.9g, 160mmol) below 10 degrees, stir for 30 minutes, and add trifluoromethylbenzophenone (18.8g) dropwise , 100 mmol) in anhydrous ethanol solution (80 ml), remove the ice bath, stir at room temperature overnight, filter, wash with a small amount of ethanol, and dry to obtain compound VII-A (28 g, yield 97%). LC/MS(ESI): m/z 289[M+1] + .
步骤2)II-A的制备Step 2) Preparation of II-A
将中间体VII-A(288mg，1mmol)和3-吡啶甲脒盐酸盐(157mg,1mmol)溶解在30ml乙醇中，加入乙醇钠(312mg，4.59mmol)，反应悬浮液在70℃下搅拌过夜，LCMS显示得到60％的中间体II-A和40％的中间体III-A。减压浓缩至干，得II-A和III-A混合物，不需要纯化直接用于下一步反应。II-A：LC/MS(ESI):m/z 374[M+1]+，III-A：346[M+1]+、344[M-1]+。Intermediate VII-A (288 mg, 1 mmol) and 3-pyridinecarboxamidine hydrochloride (157 mg, 1 mmol) were dissolved in 30 ml of ethanol, sodium ethoxide (312 mg, 4.59 mmol) was added, and the reaction suspension was stirred at 70°C overnight. , LCMS showed that 60% of intermediate II-A and 40% of intermediate III-A were obtained. Concentrate to dryness under reduced pressure to obtain a mixture of II-A and III-A, which can be directly used in the next reaction without purification. II-A: LC/MS(ESI): m/z 374[M+1] + , III-A: 346[M+1] + , 344[M-1] + .
步骤3)化合物III-A的制备Step 3) Preparation of Compound III-A
将步骤2)中得到的II-A和III-A的混合物溶解在甲醇/四氢呋喃/水(1/1/1)混合溶剂中，加入氢氧化锂一水合物(4当量)，室温搅拌5h，1N的盐酸中和至pH 7，减压浓缩至小体积，过滤，固体用乙醇-水(1:1)洗涤，干燥得中间体III-A(205mg，79％)，LC/MS(ESI):m/z346[M+1]+，344[M-1]+。Dissolve the mixture of II-A and III-A obtained in step 2) in a mixed solvent of methanol/tetrahydrofuran/water (1/1/1), add lithium hydroxide monohydrate (4 equivalents), and stir at room temperature for 5 hours. Neutralize to pH 7 with 1N hydrochloric acid, concentrate to a small volume under reduced pressure, filter, wash the solid with ethanol-water (1:1), and dry to obtain intermediate III-A (205 mg, 79%), LC/MS (ESI) :m/z346[M+1] + , 344[M-1] + .
实施例2：中间体III-A的制备，按照制备方法C
Example 2: Preparation of intermediate III-A according to preparation method C
步骤1)化合物XI-A的制备Step 1) Preparation of compound XI-A
室温下向乙醛酸(8.83g，96mmol)的醋酸(50ml)溶液加入对三氟甲基苯乙酮(11.3g,60mmol)，在120℃搅拌过夜，减压浓缩至干，加水，搅拌30min，过滤，水洗，干燥，得化合物XI-A(12.3g，收率84％)，LC/MS(ESI):m/z 243[M-1]+。Add p-trifluoromethylacetophenone (11.3g, 60mmol) to a solution of glyoxylic acid (8.83g, 96mmol) in acetic acid (50ml) at room temperature, stir at 120°C overnight, concentrate to dryness under reduced pressure, add water, and stir for 30 minutes , filtered, washed with water and dried to obtain compound XI-A (12.3g, yield 84%), LC/MS (ESI): m/z 243[M-1] + .
步骤2)化合物III-A的制备Step 2) Preparation of compound III-A
向化合物XI-A(245mg,1mmol)和3-吡啶甲脒盐酸盐(157.6mg,1mmol)的乙醇(30ml)溶液中加入乙醇钠(310mg,4.6mmol)，在70℃搅拌过夜。减压浓缩，加水和乙酸乙酯搅拌30min，过滤，得产物III-A(200mg，收率58％)，1H NMR(400MHz,DMSO-d6):δ9.10(d，J＝1.6Hz,1H),8.60-9.00(m,1H),8.80-8.81(dd,J＝4.8,1.6Hz,1H),8.66(d,J＝8.0Hz,2H),8.57(s,1H),7.98(d,J＝8.0Hz,2H)，7.64-7.67(m,1H).LC/MS(ESI):m/z 346[M+1]+。To a solution of compound XI-A (245 mg, 1 mmol) and 3-pyridinecarboxamidine hydrochloride (157.6 mg, 1 mmol) in ethanol (30 ml), sodium ethoxide (310 mg, 4.6 mmol) was added, and the mixture was stirred at 70° C. overnight. Concentrate under reduced pressure, add water and ethyl acetate, stir for 30 minutes, and filter to obtain product III-A (200 mg, yield 58%), 1 H NMR (400MHz, DMSO-d 6 ): δ9.10 (d, J=1.6Hz ,1H),8.60-9.00(m,1H),8.80-8.81(dd,J＝4.8,1.6Hz,1H),8.66(d,J＝8.0Hz,2H),8.57(s,1H),7.98( d, J=8.0Hz, 2H), 7.64-7.67 (m, 1H). LC/MS (ESI): m/z 346[M+1] + .
实施例3：中间体III-B的制备，按照制备方法B
Example 3: Preparation of intermediate III-B according to preparation method B
步骤1)化合物XI-B的制备Step 1) Preparation of compound XI-B
室温下向乙醛酸(8.83g，96mmol)的醋酸(50ml)溶液加入对氯苯乙酮(9.3g,60mmol)，在120℃搅拌过夜，减压浓缩至干，加水，搅拌30min，过滤，水洗，干燥，得化合物XI-B(9.4g，收率75％)，LC/MS(ESI):m/z209[M-1]+。Add p-chloroacetophenone (9.3g, 60mmol) to a solution of glyoxylic acid (8.83g, 96mmol) in acetic acid (50ml) at room temperature, stir at 120°C overnight, concentrate to dryness under reduced pressure, add water, stir for 30min, and filter. Wash with water and dry to obtain compound XI-B (9.4g, yield 75%), LC/MS (ESI): m/z209[M-1] + .
步骤2)化合物III-B的制备Step 2) Preparation of compound III-B
向化合物XI-B(210mg,1mmol)和3-吡啶甲脒盐酸盐(157.6mg,1mmol)的乙醇(30ml)溶液中，加入乙醇钠(310mg,4.6mmol)，在70℃搅拌过夜，反应完毕后减压浓缩，加水和乙酸乙酯搅拌30min，过滤，得产物III-B(149mg，收率48％)，LC/MS(ESI):m/z 312[M+1]+。To a solution of compound XI-B (210 mg, 1 mmol) and 3-pyridinecarboxamidine hydrochloride (157.6 mg, 1 mmol) in ethanol (30 ml), add sodium ethoxide (310 mg, 4.6 mmol), stir at 70°C overnight, and react. After completion, concentrate under reduced pressure, add water and ethyl acetate, stir for 30 minutes, filter, and obtain product III-B (149 mg, yield 48%), LC/MS (ESI): m/z 312 [M+1] + .
以下中间体III-C～III-G可以采用实施例3中类似的方法B制备

The following intermediates III-C to III-G can be prepared using a similar method B in Example 3

实施例4：中间体III-H的制备，按照制备方法C
Example 4: Preparation of intermediate III-H according to preparation method C
步骤1)中间体VIII-H的制备Step 1) Preparation of intermediate VIII-H
向尿素(66mg,1.1mmol)和化合物VII-C(305mg,1mmol)的乙醇溶液(4ml)中加入1ml的浓盐酸，在80℃搅拌过夜，冷却至室温，过滤，用冷乙醇洗涤，干燥得VIII-H。LC/MS(ESI):m/z 329[M+1]+。Add 1 ml of concentrated hydrochloric acid to the ethanol solution (4 ml) of urea (66 mg, 1.1 mmol) and compound VII-C (305 mg, 1 mmol), stir at 80°C overnight, cool to room temperature, filter, wash with cold ethanol, and dry to obtain VIII-H. LC/MS(ESI): m/z 329[M+1] + .
步骤2)中间体IX-H的制备Step 2) Preparation of intermediate IX-H
化合物VIII-H(81mg,0.25mmol)加入到2ml三氯氧磷中，氮气保护下加热到85℃，搅拌6h，减压浓缩至干，加入乙酸乙酯(10ml)和20g碎冰块，搅拌20min，过滤，干燥得化合物IX-H。LC/MS(ESI):m/z 347[M+1]+。Compound VIII-H (81 mg, 0.25 mmol) was added to 2 ml of phosphorus oxychloride, heated to 85°C under nitrogen protection, stirred for 6 hours, concentrated to dryness under reduced pressure, added ethyl acetate (10 ml) and 20 g of crushed ice, and stirred 20 min, filter and dry to obtain compound IX-H. LC/MS(ESI): m/z 347[M+1] + .
步骤3)中间体III-H的制备Step 3) Preparation of intermediate III-H
化合物IX-H(348mg，1mmol)和1-甲基吡唑-4-硼酸频哪醇酯(208mg，1mmol)的二氧六环(5ml)和饱和碳酸钠水溶液(1ml)，氮气保护下，加入四(三苯基膦)钯(10mg)及PdCl2(dppf)2)(10mg)，加热到100℃，搅拌过夜。有机相减压浓缩至干，硅胶柱层析纯化得化合物III-H。LC/MS(ESI):m/z 365[M+1]+，363[M-1]+。Compound IX-H (348mg, 1mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (208mg, 1mmol) in dioxane (5ml) and saturated sodium carbonate aqueous solution (1ml), under nitrogen protection, Tetrakis(triphenylphosphine)palladium (10 mg) and PdCl 2 (dppf) 2 ) (10 mg) were added, heated to 100°C, and stirred overnight. The organic phase was concentrated to dryness under reduced pressure and purified by silica gel column chromatography to obtain compound III-H. LC/MS(ESI): m/z 365[M+1] + , 363[M-1] + .
以下中间体III-I～III-P可以采用实施例4中类似的方法C制备


The following intermediates III-I to III-P can be prepared using similar method C in Example 4


实施例5：中间体III-Q的制备，按照制备方法D
Example 5: Preparation of intermediate III-Q according to preparation method D
步骤1)中间体XIII-Q的制备Step 1) Preparation of intermediate XIII-Q
将NaOH溶液(2.17g,54mmol，水4.5ml)滴加到草酰乙酸二乙酯钠盐(6.65g,31.7mmol)的水(40ml)悬浮液中,搅拌至固体完全溶解，加3-甲脒吡啶盐酸盐(3.85g,31.8mmol)，混合物加热到70℃，搅拌过夜，冷却至室温，浓盐酸调节pH＝1，过滤，固体用乙酸乙酯洗涤，得中间体XIII-Q(4.42g，收率83％)。1H NMR(DMSO-d6):δ9.30(d,J＝2.0Hz，1H),8.76(dd,J＝1.2,4.8Hz，1H),8.50(dt,J＝7.6,1.2Hz，1H),7.60(dd,J＝4.8,7.6Hz，1H),6.96(s,1H)。LC/MS(ESI):m/z 218[M+1]+，216[M-1]+。NaOH solution (2.17g, 54mmol, water 4.5ml) was added dropwise to the suspension of diethyl oxaloacetate sodium salt (6.65g, 31.7mmol) in water (40ml), stirred until the solid was completely dissolved, and 3-methyl Amidopyridine hydrochloride (3.85g, 31.8mmol), the mixture was heated to 70°C, stirred overnight, cooled to room temperature, adjusted to pH=1 with concentrated hydrochloric acid, filtered, and the solid was washed with ethyl acetate to obtain intermediate XIII-Q (4.42 g, yield 83%). 1 H NMR (DMSO-d6): δ9.30 (d, J = 2.0 Hz, 1H), 8.76 (dd, J = 1.2, 4.8 Hz, 1H), 8.50 (dt, J = 7.6, 1.2 Hz, 1H) ,7.60(dd,J=4.8,7.6Hz,1H),6.96(s,1H). LC/MS(ESI): m/z 218[M+1] + , 216[M-1] + .
步骤2)中间体XIV-Q的制备Step 2) Preparation of intermediate XIV-Q
化合物XIII-Q(218mg,1mmol)的POCl3(5ml)悬浮液在氮气保护下，85℃搅拌过夜，减压浓缩至干，加50ml EA,搅拌10min，加甲醇1ml，搅拌，水洗，无水硫酸钠干燥，过滤，减压浓缩得中间体XIV-Q，不纯化直接用于下一步。A suspension of compound XIII-Q (218mg, 1mmol) in POCl 3 (5ml) was stirred overnight at 85°C under nitrogen protection, concentrated to dryness under reduced pressure, added 50ml EA, stirred for 10min, added 1ml methanol, stirred, washed with water, anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain intermediate XIV-Q, which is used directly in the next step without purification.
步骤3)中间体III-Q的制备Step 3) Preparation of intermediate III-Q
化合物XIV-Q(250mg，1mmol)和3-氟苯硼酸(140mg，1mmol)的二氧六环(10ml)和饱和碳酸钠水溶液(1ml)，氮气保护下，加入四(三苯基膦)钯(15mg)，加热到100℃，搅拌过夜。有机相减压浓缩至干，硅胶柱层析纯化得中间体III-Q。LC/MS(ESI):m/z 296[M+1]+，294[M-1]+。Compound XIV-Q (250 mg, 1 mmol) and 3-fluorophenylboronic acid (140 mg, 1 mmol) in dioxane (10 ml) and saturated sodium carbonate aqueous solution (1 ml), under nitrogen protection, add tetrakis (triphenylphosphine) palladium (15mg), heated to 100°C and stirred overnight. The organic phase was concentrated to dryness under reduced pressure and purified by silica gel column chromatography to obtain intermediate III-Q. LC/MS(ESI): m/z 296[M+1] + , 294[M-1] + .
以下中间体III-R～III-V可以采用实施例5中类似的方法D制备

The following intermediates III-R to III-V can be prepared using a similar method D in Example 5

实施例6：中间体III-W和III-Y的制备，按照制备方法E和FExample 6: Preparation of intermediates III-W and III-Y according to preparation methods E and F
方法E
Method E
步骤1)中间体XIV-W的制备Step 1) Preparation of intermediate XIV-W
2,6-二氯嘧啶-4-甲酸(1.93g，10mmol)和3-三氟苯硼酸(2.27g，11mmol)的甲苯(50ml)和饱和碳酸钠水溶液(10ml)，加入四(三苯基膦)钯(50mg)及PdCl2(dppf)2)(50mg)，氮气保护下加热到110℃，搅拌过夜。有机相减压浓缩至干，硅胶柱层析纯化得中间体XIV-W(2.04g，376％)和副产物(XV-Y)1.4g。XIV-W：1HNMR:(400MHz,DMSO-d6)δ8.34(s,1H),7.20-7.44(m,3H),6.97(m,1H)。LC/MS(ESI):m/z251[M-1]+。2,6-Dichloropyrimidine-4-carboxylic acid (1.93g, 10mmol) and 3-trifluorophenylboronic acid (2.27g, 11mmol) in toluene (50ml) and saturated aqueous sodium carbonate (10ml), add tetrakis(triphenyl) Phosphine) palladium (50 mg) and PdCl 2 (dppf) 2 ) (50 mg) were heated to 110°C under nitrogen protection and stirred overnight. The organic phase was concentrated to dryness under reduced pressure and purified by silica gel column chromatography to obtain 1.4 g of intermediate XIV-W (2.04 g, 376%) and by-product (XV-Y). XIV-W: 1 HNMR: (400MHz, DMSO-d 6 ) δ 8.34 (s, 1H), 7.20-7.44 (m, 3H), 6.97 (m, 1H). LC/MS(ESI):m/z251[M-1] + .
步骤2)III-W的制备Step 2) Preparation of III-W
将化合物XIV-W(504mg，2mmol)和1-甲基吡唑-4-硼酸频哪醇酯(624mg，3mmol)溶解在20ml的二氧六环中，加入饱碳酸钠溶液(1ml)和四(三苯基磷)钯(231mg，0.2mmol)，氮气保护下，100℃搅拌过夜。减压浓缩至干，用2N HCl调节pH～6-7，过滤，DCM洗涤，粗品用硅胶柱层析纯化，得到化合物III-W。LC/MS(ESI):m/z299[M+1]+，297[M-1]+。Compound XIV-W (504 mg, 2 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (624 mg, 3 mmol) were dissolved in 20 ml of dioxane, and saturated sodium carbonate solution (1 ml) and tetrahydrofuran were added. (Triphenylphosphine)palladium (231 mg, 0.2 mmol), stirred at 100°C overnight under nitrogen protection. Concentrate to dryness under reduced pressure, adjust pH to 6-7 with 2N HCl, filter, and wash with DCM. The crude product is purified by silica gel column chromatography to obtain compound III-W. LC/MS(ESI): m/z299[M+1] + , 297[M-1] + .
方法F
Method F
步骤1)中间体XV-Y的制备:参照方法E制得(见方法E步骤1)。XV-Y：LC/MS(ESI):m/z 253[M+1]+。Step 1) Preparation of intermediate XV-Y: Prepare according to method E (see step 1 of method E). XV-Y: LC/MS(ESI): m/z 253[M+1] + .
步骤2)III-W的制备Step 2) Preparation of III-W
将化合物XV-Y(504mg，2mmol)和6-(三氟甲基)吡啶-3-硼酸(573mg，3mmol)溶解在20ml的二氧六环中，加入饱碳酸钠溶液(1ml)和四(三苯基磷)钯(231mg，0.2mmol)，氮气保护下，100℃搅拌过夜。减压浓缩至干，用2N HCl调节pH～6-7，过滤，DCM洗涤，硅胶柱层析纯化，得化合物III-Y。LC/MS(ESI):m/z 364[M+1]+，362[M-1]+。Compound XV-Y (504 mg, 2 mmol) and 6-(trifluoromethyl)pyridine-3-boronic acid (573 mg, 3 mmol) were dissolved in 20 ml of dioxane, and saturated sodium carbonate solution (1 ml) and tetrakis ( Triphenylphosphonium palladium (231 mg, 0.2 mmol), stirred at 100°C overnight under nitrogen protection. Concentrate to dryness under reduced pressure, adjust pH to 6-7 with 2N HCl, filter, wash with DCM, and purify by silica gel column chromatography to obtain compound III-Y. LC/MS(ESI): m/z 364[M+1] + , 362[M-1] + .
实施例7：中间体IV-1的制备
Example 7: Preparation of Intermediate IV-1
步骤1)中间体XVI-1的制备Step 1) Preparation of intermediate XVI-1
将BocNHNH2(13.2g,100mmol)溶解在100ml丙酮和50ml的甲醇中，加入无水硫酸镁(12g，100mmol)，室温搅拌过夜，过滤除去硫酸镁，滤液减压浓缩至干，加100ml甲醇溶解，室温下分批加入硼氢化钠(15.2g，400mmol)，加毕，室温搅拌1h，减压浓缩至干，加入200ml蒸馏水，用二氯甲烷萃取100mlx3次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩至干。硅胶柱层析纯化(20％乙酸乙酯/石油醚)得XVI-1(15.1g,收率87％)。LC/MS(ESI):m/z 175[M+1]+。Dissolve BocNHNH 2 (13.2g, 100mmol) in 100ml acetone and 50ml methanol, add anhydrous magnesium sulfate (12g, 100mmol), stir at room temperature overnight, filter to remove magnesium sulfate, concentrate the filtrate to dryness under reduced pressure, add 100ml methanol to dissolve , add sodium borohydride (15.2g, 400mmol) in batches at room temperature, complete the addition, stir at room temperature for 1 hour, concentrate to dryness under reduced pressure, add 200ml distilled water, extract 100mlx3 times with dichloromethane, combine the organic phases, and dry over anhydrous sodium sulfate , filtered and concentrated to dryness under reduced pressure. Purification by silica gel column chromatography (20% ethyl acetate/petroleum ether) gave XVI-1 (15.1 g, yield 87%). LC/MS(ESI): m/z 175[M+1] + .
步骤2)中间体XVII-1的制备Step 2) Preparation of intermediate XVII-1
将中间体XVI-1(1.74g,10mmol)、环氧丙烷(2.9g,50mmol)、N,N-二异丙基乙胺(DIPEA)(2.58g，20mmol)溶于20ml乙醇中，在密封的反应瓶中，80℃搅拌过夜。减压浓缩至干，硅胶柱层析纯化(20％-50％乙酸乙酯/石油醚)得XVII-1(1.82g,收率78％)。LC/MS(ESI):m/z 233[M+1]+。Dissolve intermediate XVI-1 (1.74g, 10mmol), propylene oxide (2.9g, 50mmol), N,N-diisopropylethylamine (DIPEA) (2.58g, 20mmol) in 20ml of ethanol, seal reaction bottle, stir at 80°C overnight. Concentrate to dryness under reduced pressure and purify by silica gel column chromatography (20%-50% ethyl acetate/petroleum ether) to obtain XVII-1 (1.82g, yield 78%). LC/MS(ESI): m/z 233[M+1] + .
步骤3)中间体IV-1的制备Step 3) Preparation of intermediate IV-1
将1.82g化合物XVII-1溶解在10ml甲醇中，加入HCl的甲醇溶液(过量)，室温搅拌过夜，40℃减压浓缩至干，得中间体IV-1盐酸盐(2.3g，收率95％)。LC/MS(ESI):m/z 133[M+1]+。Dissolve 1.82g of compound XVII-1 in 10 ml of methanol, add HCl methanol solution (excess), stir at room temperature overnight, and concentrate to dryness under reduced pressure at 40°C to obtain intermediate IV-1 hydrochloride (2.3g, yield 95 %). LC/MS(ESI): m/z 133[M+1] + .
实施例8：中间体IV-2的制备
Example 8: Preparation of intermediate IV-2
步骤1)中间体XVI-2的制备Step 1) Preparation of intermediate XVI-2
向500ml的圆底烧瓶中依次加入BocNHNH2(30g,227mmol)、300ml甲醇、20.4g羟基丙酮和无水硫酸镁(68g)，室温搅拌3.5h，过滤除去硫酸镁，滤饼用无水甲醇洗涤，在0℃下分批向滤液中加硼氢化钠(15.2g，400mmol)，加毕，室温搅拌1h，减压浓缩至干，加入200ml蒸馏水，用二氯甲烷萃取100mlx3次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩至干。硅胶柱层析纯化(20-40％乙酸乙酯/石油醚)得XVI-2(36g,收率84％)。LC/MS(ESI):m/z 191[M+1]+。Add BocNHNH 2 (30g, 227mmol), 300ml methanol, 20.4g hydroxyacetone and anhydrous magnesium sulfate (68g) to a 500ml round-bottomed flask in sequence, stir at room temperature for 3.5h, filter to remove magnesium sulfate, and wash the filter cake with anhydrous methanol. , add sodium borohydride (15.2g, 400mmol) to the filtrate in batches at 0°C, complete the addition, stir at room temperature for 1 hour, concentrate to dryness under reduced pressure, add 200ml of distilled water, extract 100mlx3 times with dichloromethane, combine the organic phases, Dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate/petroleum ether) gave XVI-2 (36g, yield 84%). LC/MS(ESI): m/z 191[M+1] + .
步骤2)中间体XVII-2的制备Step 2) Preparation of intermediate XVII-2
向1L的圆底烧瓶中间体XVI-2(19.0g,100mmol)、丙酮(17.4g，300mmol)、甲醇300ml，1ml醋酸，室温下加入氰基硼氢化钠(15.7g，250mmol)，反应混合物室温搅拌过夜。减压浓缩至干，加入蒸馏水，用乙酸乙酯萃取，干燥，过滤，浓缩。硅胶柱层析纯化(10％-50％乙酸乙酯/石油醚)得白色固体XVII-2(14.1g,收率61％)。LC/MS(ESI):m/z 233[M+1]+。To a 1L round bottom flask, intermediate XVI-2 (19.0g, 100mmol), acetone (17.4g, 300mmol), 300ml methanol, 1ml acetic acid, sodium cyanoborohydride (15.7g, 250mmol) was added at room temperature, and the reaction mixture was room temperature. Stir overnight. Concentrate to dryness under reduced pressure, add distilled water, extract with ethyl acetate, dry, filter and concentrate. Silica gel column chromatography purified (10%-50% ethyl acetate/petroleum ether) to obtain white solid XVII-2 (14.1g, yield 61%). LC/MS(ESI): m/z 233[M+1] + .
步骤3)中间体IV-2的制备：方法同实施例7中步骤3)的化合物IV-1步骤，收率90％。LC/MS(ESI):m/z 133[M+1]+。Step 3) Preparation of intermediate IV-2: The method is the same as that of compound IV-1 in step 3) in Example 7, and the yield is 90%. LC/MS(ESI): m/z 133[M+1] + .
实施例9：中间体IV-3的制备
Example 9: Preparation of intermediate IV-3
步骤1)中间体XVII-3的制备Step 1) Preparation of intermediate XVII-3
在0℃下，向2-羟基乙基肼(5g，65mmol)的甲醇(100ml)溶液中，加入13ml三乙胺、Boc2O(17.2g，78mmol)，氮气保护下室温搅拌16h，减压浓缩至干，加柠檬酸溶液，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩至干。硅胶柱层析纯化(20-40％乙酸乙酯/石油醚)得XVII-3(6.8g,收率89％)。LC/MS(ESI):m/z 177[M+1]+。To a solution of 2-hydroxyethylhydrazine (5g, 65mmol) in methanol (100ml) at 0°C, add 13ml of triethylamine and Boc 2 O (17.2g, 78mmol), stir at room temperature for 16h under nitrogen protection, and reduce the pressure. Concentrate to dryness, add citric acid solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate/petroleum ether) gave XVII-3 (6.8 g, yield 89%). LC/MS(ESI): m/z 177[M+1] + .
步骤2)中间体XVII-3的制备Step 2) Preparation of intermediate XVII-3
将中间体XVII-3(2g,11.2mmol)溶解在50ml的THF中，加入氢化铝锂(LAH)(1.7g，44.8mmol)，氮气保护下回流5h，冷却至0℃下，分批加入Na2SO4·10H2O，过滤，滤饼用THF洗涤，滤液无水硫酸镁干燥，浓缩得IV-3粗品,无需纯化直接用于下一步。LC/MS(ESI):m/z 91[M+1]+。Dissolve intermediate XVII-3 (2g, 11.2mmol) in 50 ml of THF, add lithium aluminum hydride (LAH) (1.7g, 44.8mmol), reflux under nitrogen protection for 5 hours, cool to 0°C, and add Na in batches 2 SO 4 ·10H 2 O, filter, wash the filter cake with THF, dry the filtrate over anhydrous magnesium sulfate, and concentrate to obtain IV-3 crude product, which can be used directly in the next step without purification. LC/MS(ESI): m/z 91[M+1] + .
实施例9：中间体IV-4的制备
Example 9: Preparation of Intermediate IV-4
步骤1)中间体XVII-4的制备Step 1) Preparation of intermediate XVII-4
在0℃下，将2-羟基乙基肼(7.6g，100mmol)加入甲醇(100ml)和丙酮(50ml)混合溶剂中，加入无水硫酸镁(12g，100mmol)，室温搅拌过夜，过滤除去硫酸镁，滤液减压浓缩至干，加100ml二氯甲烷溶解，加三乙胺(20.2g，200mmol)，在0℃下滴加醋酸酐(10.7g，105mmol)，室温搅拌过夜，加入200ml蒸馏水，用二氯甲烷萃取，合并有机相减压浓缩至干，加入四氢呋喃(50ml)和5ml盐酸，室温搅拌12h，减压浓缩至干得XVII-4，不纯化直接用于下一步。LC/MS(ESI):m/z 119[M+1]+。At 0°C, add 2-hydroxyethylhydrazine (7.6g, 100mmol) to a mixed solvent of methanol (100ml) and acetone (50ml), add anhydrous magnesium sulfate (12g, 100mmol), stir at room temperature overnight, and filter to remove sulfuric acid. Magnesium, the filtrate was concentrated to dryness under reduced pressure, added 100ml dichloromethane to dissolve, added triethylamine (20.2g, 200mmol), added acetic anhydride (10.7g, 105mmol) dropwise at 0°C, stirred at room temperature overnight, added 200ml distilled water, Extract with dichloromethane, combine the organic phases and concentrate to dryness under reduced pressure. Add tetrahydrofuran (50ml) and 5ml of hydrochloric acid, stir at room temperature for 12 hours, and concentrate to dryness under reduced pressure to obtain XVII-4, which is used directly in the next step without purification. LC/MS(ESI): m/z 119[M+1] + .
步骤2)中间体IV-4的制备Step 2) Preparation of intermediate IV-4
将中间体XVII-4(1.2g,10mmol)溶解在50ml的THF中，加入四氢铝锂(LAH)(1.5g，44.8mmol)，氮气保护下回流4h，冷却至0℃以下，分批加入Na2SO4·10H2O淬灭反应，过滤，滤饼用THF洗涤，滤液用无水硫酸镁干燥，过滤，减压浓缩至干得IV-4。LC/MS(ESI):m/z 105[M+1]+。Dissolve intermediate XVII-4 (1.2g, 10mmol) in 50ml of THF, add lithium aluminum tetrahydride (LAH) (1.5g, 44.8mmol), reflux under nitrogen protection for 4 hours, cool to below 0°C, and add in batches Na 2 SO 4 ·10H 2 O quenched the reaction, filtered, the filter cake was washed with THF, the filtrate was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain IV-4. LC/MS(ESI): m/z 105[M+1] + .
实施例10：中间体IV-5的制备
Example 10: Preparation of Intermediate IV-5
步骤1)中间体XVII-5的制备Step 1) Preparation of intermediate XVII-5
中间体XVI-1(12.8g，73.5mmol)，溴乙酸乙酯(36.6g，219mmol)，无水碳酸钾(30.2g，219mmol)，溶解在250ml DMF中，氮气保护下，加热到80℃，搅拌过夜，冷至室温，加水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩至干得XVII-5粗品18g。LC/MS(ESI):m/z 261[M+1]+。Intermediate XVI-1 (12.8g, 73.5mmol), ethyl bromoacetate (36.6g, 219mmol), and anhydrous potassium carbonate (30.2g, 219mmol) were dissolved in 250ml DMF and heated to 80°C under nitrogen protection. Stir overnight, cool to room temperature, add water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure to obtain 18 g of crude product XVII-5. LC/MS(ESI): m/z 261[M+1] + .
步骤2)中间体XVII-5的制备Step 2) Preparation of intermediate XVII-5
在2L的圆底烧瓶中依次加入380ml乙醇、NaBH4(7.2g，189mmol)及LiCl(7.9g，188mmol)，然后室温下滴加XVII-5(18g，69mmol)的THF溶液(380ml)，搅拌6h，减压浓缩除去大量溶解，加水，乙酸乙酯萃取，合并后的有机相用无水Na2SO4干燥，过滤，减压浓缩至干得XVII-5(12.9g，收率86％)。LC/MS(ESI):m/z 219[M+1]+。Add 380ml of ethanol, NaBH4 (7.2g, 189mmol) and LiCl (7.9g, 188mmol) in sequence to a 2L round-bottomed flask, then add XVII-5 (18g, 69mmol) in THF solution (380ml) dropwise at room temperature, and stir for 6h , concentrated under reduced pressure to remove a large amount of dissolved matter, added water, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to dryness to obtain XVII-5 (12.9 g, yield 86%). LC/MS(ESI): m/z 219[M+1] + .
步骤3)中间体IV-5的制备Step 3) Preparation of intermediate IV-5
将XVIII-5(12.9g)溶解在50ml二氧六环中，加入HCl的二氧六环溶液(6N，30ml)，室温搅拌过夜，减压浓缩至干，得中间体IV-5(12.8g)。LC/MS(ESI):m/z 119[M+1]+。Dissolve XVIII-5 (12.9g) in 50ml of dioxane, add HCl in dioxane (6N, 30ml), stir at room temperature overnight, and concentrate to dryness under reduced pressure to obtain intermediate IV-5 (12.8g ). LC/MS(ESI): m/z 119[M+1] + .
实施例11：中间体IV-6的制备
Example 11: Preparation of Intermediate IV-6
步骤1)中间体XIX-6的制备Step 1) Preparation of intermediate XIX-6
向3-甲基吗啉(1.0g，10mmol)的THF溶液(15ml)中，加入亚硝酸叔丁酯(1.1g,11mmol),回流12h，减压浓缩至干,得到XIX-6，不纯化直接用于下一步。LC/MS(ESI):m/z 131[M+1]+。To a THF solution (15ml) of 3-methylmorpholine (1.0g, 10mmol), add tert-butyl nitrite (1.1g, 11mmol), reflux for 12h, and concentrate to dryness under reduced pressure to obtain XIX-6 without purification. used directly in the next step. LC/MS(ESI): m/z 131[M+1] + .
步骤2)中间体IV-6的制备 Step 2) Preparation of intermediate IV-6
将上一步的中间体XIX-6(80mmol)溶解在200ml的THF中，在0℃下分批加入LAH(6.1g，160mmol)，室温搅拌过夜，冷却下，分批加入Na2SO4·10H2O，过滤，滤饼用THF洗涤，滤液无水硫酸镁干燥，过滤，减压浓缩得化合物的IV-6(收率72％)。LC/MS(ESI):m/z 117[M+1]+。Dissolve the intermediate XIX-6 (80mmol) from the previous step in 200 ml of THF, add LAH (6.1g, 160mmol) in batches at 0°C, stir at room temperature overnight, cool, and add Na 2 SO 4 ·10H in batches 2 O, filtered, the filter cake was washed with THF, the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound IV-6 (yield 72%). LC/MS(ESI): m/z 117[M+1] + .
用实施例11的方法可以制备下面的肼

The following hydrazine can be prepared using the method of Example 11

实施例12：6-(4-三氟甲基苯基)-N-(1-羟基丙基-2-基)-N-异丙基-2-(吡啶-3-基)嘧啶-4-酰肼(化合物1)的制备
Example 12: 6-(4-trifluoromethylphenyl)-N-(1-hydroxypropyl-2-yl)-N-isopropyl-2-(pyridin-3-yl)pyrimidine-4- Preparation of hydrazide (compound 1)
中间体III-A(36mg,0.1mmol)、肼盐酸盐(IV-2)(20mg，0.12mmol)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(57mg,0.15mmol)溶解在2ml的N,N-二甲基甲酰胺(DMF)中，加入DIPEA(47mg,0.36mmol),在氮气下搅拌过夜，用乙酸乙酯稀释，水洗，有机相用无水硫酸钠干燥，过滤，减压浓缩至干，制备硅胶层析纯化(PE/EA，1:1)，得化合物1(23mg，收率50％)。LC/MS(ESI):m/z 459[M+1]+。1H NMR(400MHz,DMSO-d6):δ10.22(s,1H),9.88(d,1H),9.03(t,1H),9.00(dt,1H),8.82(dd,1H),8.66(d,2H),8.56(s,1H),7.96(d,2H),4.34-4.37(m,1H),3.40-3.48(m,1H),3.28-3.35(m,1H),3.16-3.23(m,2H),1.14-1.20(m,6H),0.98(d,J＝6.8Hz,3H)。Intermediate III-A (36 mg, 0.1 mmol), hydrazine hydrochloride (IV-2) (20 mg, 0.12 mmol), 2-(7-oxybenzotriazole)-N,N,N',N' -Tetramethylurea hexafluorophosphate (HATU) (57 mg, 0.15 mmol) was dissolved in 2 ml of N, N-dimethylformamide (DMF), added DIPEA (47 mg, 0.36 mmol), and stirred under nitrogen overnight , diluted with ethyl acetate, washed with water, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel chromatography (PE/EA, 1:1) to obtain compound 1 (23 mg, yield 50 %). LC/MS(ESI): m/z 459[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.22(s,1H),9.88(d,1H),9.03(t,1H),9.00(dt,1H),8.82(dd,1H),8.66( d,2H),8.56(s,1H),7.96(d,2H),4.34-4.37(m,1H),3.40-3.48(m,1H),3.28-3.35(m,1H),3.16-3.23( m,2H),1.14-1.20(m,6H),0.98(d,J＝6.8Hz,3H).
下表1中的化合物可以用实施例1类似的方法制得。The compounds in Table 1 below can be prepared using a similar method to Example 1.
表1









Table 1









实施例13：化合物66的制备
Example 13: Preparation of Compound 66
化合物10(40.2mg，0.1mmol)溶解在5ml的二氯甲烷(DCM)中，加入0.1ml的DIPEA，冷却至0℃，滴加0.06ml的乙酸酐，加毕，室温搅拌反应过夜，水洗三次，无水硫酸钠干燥，过滤、减压浓缩至干，硅胶柱层析纯化(PE/EA,1:1)的化合物66。收率64％。LC/MS(ESI):m/z 444[M+1]+。1H NMR(400MHz,DMSO-d6):δ10.08(s,1H),9.95(d,J＝1.6Hz,1H),9.07(ddd,J＝1.6,2.0,7.6Hz,1H),8.82(dd,J＝1.2,4.8Hz,1H),8.65(d,J＝8.0Hz,2H),8.53(s,1H),7.97(d,J＝8.0Hz,2H),7.66(dd,J＝7.6,4.8Hz,1H),3.18-3.27(m,1H),2.08(s,3H),1.18(d,J＝6.4Hz,6H)。Compound 10 (40.2 mg, 0.1 mmol) was dissolved in 5 ml of dichloromethane (DCM), 0.1 ml of DIPEA was added, cooled to 0°C, 0.06 ml of acetic anhydride was added dropwise, the addition was completed, the reaction was stirred at room temperature overnight, and washed three times with water. , dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and compound 66 was purified by silica gel column chromatography (PE/EA, 1:1). Yield 64%. LC/MS(ESI): m/z 444[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.08(s,1H),9.95(d,J＝1.6Hz,1H),9.07(ddd,J＝1.6,2.0,7.6Hz,1H),8.82( dd,J＝1.2,4.8Hz,1H),8.65(d,J＝8.0Hz,2H),8.53(s,1H),7.97(d,J＝8.0Hz,2H),7.66(dd,J＝7.6 ,4.8Hz,1H),3.18-3.27(m,1H),2.08(s,3H),1.18(d,J＝6.4Hz,6H).
实施例14：化合物67的制备
Example 14: Preparation of Compound 67
按照实施例13类似的方法制备化合物67，由化合物10和甲磺酰氯反应得化合物67，收率41％，LC/MS(ESI):m/z 480[M+1]+。1H NMR(400MHz,DMSO-d6):δ10.20(s,1H),9.96(d,J＝1.6Hz,1H),9.067(ddd,J＝1.6,2.0,7.6Hz,1H),8.82(dd,J＝1.2,4.8Hz,1H),8.65(d,J＝8.0Hz,2H),8.53(s,1H),7.97(d,J＝8.0Hz,2H),7.66(dd,J＝7.6,4.8Hz,1H),3.18-3.27(m,1H),2.92(s,3H),1.18(d,J＝6.4Hz,6H)。 Compound 67 was prepared according to a method similar to Example 13. Compound 67 was obtained by reacting compound 10 with methanesulfonyl chloride. The yield was 41%. LC/MS (ESI): m/z 480 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.20(s,1H),9.96(d,J＝1.6Hz,1H),9.067(ddd,J＝1.6,2.0,7.6Hz,1H),8.82( dd,J＝1.2,4.8Hz,1H),8.65(d,J＝8.0Hz,2H),8.53(s,1H),7.97(d,J＝8.0Hz,2H),7.66(dd,J＝7.6 ,4.8Hz,1H),3.18-3.27(m,1H),2.92(s,3H),1.18(d,J=6.4Hz,6H).
实施例15：化合物68的制备
Example 15: Preparation of Compound 68
按照实施例13类似的方法制备化合物68，由化合物10和氯化烟碱盐酸盐反应得化合物68，收率84％，LC/MS(ESI):m/z 507[M+1]+。Compound 68 was prepared in a similar manner to Example 13. Compound 68 was obtained by reacting compound 10 with nicotine chloride hydrochloride. The yield was 84%. LC/MS (ESI): m/z 507 [M+1] + .
效果实施例1：人源细胞系中研究化合物与AHR拮抗作用测试Effect Example 1: Test of antagonism between research compounds and AHR in human cell lines
测试使用内源表达AHR蛋白的人肝癌HepG2细胞系(由中国科学院干细胞库提供)。CYP1A1基因表达受到AHR活性的调控，AHR激活后能结合CYP1A1增强子上称为外源反应元件(xenobiotic response element,XRE)的序列并引发CYP1A1基因表达。为了定量测量化合物对AHR活性的影响，CYP1A1基因启动子上游1200bp(-1143至+57)的调控序列通过基因合成后***包含萤火虫荧光素酶的质粒载体中。质粒随后经过单酶切线性化后通过脂质体转染(Lipofectamine3000)进HepG2细胞，转染后的HepG2细胞通过嘌呤霉素筛选得到稳定表达的细胞系。在测量化合物和AHR的拮抗作用时，用AHR激动剂(如L-Kynurenine,Kynurenic acid,indirubin,TCDD,ITE(2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester))等引发萤火虫荧光素酶的表达，同时用不同浓度的化合物来处理细胞，然后测量化合物对荧光素酶表达的抑制。The test used the human liver cancer HepG2 cell line that endogenously expresses AHR protein (provided by the Stem Cell Bank of the Chinese Academy of Sciences). CYP1A1 gene expression is regulated by AHR activity. After activation, AHR can bind to a sequence called a xenobiotic response element (XRE) on the CYP1A1 enhancer and trigger CYP1A1 gene expression. In order to quantitatively measure the effect of compounds on AHR activity, the 1200 bp (-1143 to +57) regulatory sequence upstream of the CYP1A1 gene promoter was synthesized and inserted into a plasmid vector containing firefly luciferase. The plasmid was then linearized by single enzyme digestion and transfected into HepG2 cells via lipofectamine 3000. The transfected HepG2 cells were screened with puromycin to obtain stable expression cell lines. When measuring the antagonism between compounds and AHR, use AHR agonists (such as L-Kynurenine, Kynurenic acid, indirubin, TCDD, ITE (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester)), etc. Expression of firefly luciferase is elicited while cells are treated with different concentrations of compounds, and the inhibition of luciferase expression by the compounds is measured.
稳定转染的HepG2细胞在Eagle最低必须培养基(Minimum Eagle’s medium,MEM)中，37℃，5％二氧化碳的环境下传代培养。MEM培养基中补充了1mM丙酮酸钠，2mM GlutaMax，1×非必须氨基酸，10％澳洲胎牛血清，100U/mL的青链霉素以及5ug/mL的嘌呤霉素。测试前，HepG2细胞通过传代以5～8×104/孔的密度种植到96孔板中并生长24～48h以便在进行药物处理前达到～90％的汇合度(培养基中不含嘌呤霉素)。在药物处理前，先用相同培养基配制包含AHR激动剂的2×不同浓度的化合物溶液，然后将96孔板中的细胞培养基的一半替换成2×化合物溶液。阴性对照组设为仅包含对应浓度DMSO的AHR激动剂溶液，而阳性对照组设为对应浓度的CH223191(商购)。每个化合物(包括阳性对照及阴性对照)做2组独立重复测试。HepG2细胞在化合物处理24h后通过Promega公司的Steady-Glo荧光素酶检测***进行裂解，并用Tecan公司的InfiniteM1000 Pro酶标仪测量荧光素酶信号。Stably transfected HepG2 cells were subcultured in Minimum Eagle's medium (MEM) at 37°C in a 5% carbon dioxide environment. MEM medium was supplemented with 1mM sodium pyruvate, 2mM GlutaMax, 1× non-essential amino acids, 10% Australian fetal calf serum, 100U/mL penicillin and 5ug/mL puromycin. Before testing, HepG2 cells were seeded into 96-well plates at a density of 5 to 8 × 10 4 /well and grown for 24 to 48 h to reach ~90% confluence before drug treatment (the culture medium did not contain puromyces white). Before drug treatment, 2× compound solutions containing AHR agonists at different concentrations were prepared with the same culture medium, and then half of the cell culture medium in the 96-well plate was replaced with 2× compound solution. The negative control group was set as the AHR agonist solution containing only corresponding concentration of DMSO, while the positive control group was set as CH223191 (commercially available) at the corresponding concentration. Each compound (including positive control and negative control) was tested in two independent sets. HepG2 cells were lysed by Promega's Steady-Glo luciferase detection system after 24 hours of compound treatment, and the luciferase signal was measured using Tecan's InfiniteM1000 Pro microplate reader.
数据处理上，对每一个化合物的每组重复测试，以化合物浓度为0的孔信号作为100％，以未处理激动剂的细胞信号作为0，依次计算不同化合物浓度下的AHR活性抑制百分比，将2组重复数据的平均值通过非线性拟合按照公式计算化合物对应的IC50，其中y是抑制百分比，x是对应化合物的浓度。In terms of data processing, each compound was tested repeatedly for each group. The well signal with a compound concentration of 0 was taken as 100%, and the cell signal with untreated agonist was taken as 0. The AHR activity inhibition percentage at different compound concentrations was calculated in turn. The average value of 2 sets of repeated data is calculated by nonlinear fitting according to the formula Calculate the IC 50 corresponding to the compound, where y is the percent inhibition and x is the concentration of the corresponding compound.
参考文献：Buckley,S.M.K.et al.In vivo bioimaging with tissue-specific transcription factor activated luciferase reporters.Sci.Rep.5:11842(2015).Reference: Buckley, S.M.K.et al.In vivo bioimaging with tissue-specific transcription factor activated luciferase reporters.Sci.Rep.5:11842(2015).
各化合物的IC50如表2所示，其中A表示IC50≤500nM，B表示500nM＜IC50≤1.0μM，C表示1μM＜IC50≤5.0μM，D表示IC50>5.0μMThe IC 50 of each compound is shown in Table 2, where A means IC 50 ≤500nM, B means 500nM＜IC 50 ≤1.0μM, C means 1μM＜IC 50 ≤5.0μM, and D means IC 50 >5.0μM.
表2：各化合物的IC50

Table 2: IC 50 of each compound

由表2可知，上述各化合物可结合至AHR并抑制由AHR控制的那些功能和信号通路，进而可影响癌细胞的生长与增殖以及肿瘤细胞的侵袭力，因此本发明的式Ⅰ所示的化合物可用于抑制癌细胞生长，抑制肿瘤细胞的转移和侵袭。 As can be seen from Table 2, each of the above compounds can bind to AHR and inhibit those functions and signaling pathways controlled by AHR, thereby affecting the growth and proliferation of cancer cells and the invasiveness of tumor cells. Therefore, the compounds represented by Formula I of the present invention It can be used to inhibit the growth of cancer cells and inhibit the metastasis and invasion of tumor cells.

Claims (17)

  1. 一类由以下式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐：
    A class of substituted pyrimidine hydrazide compounds represented by the following formula I, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt:
    其中，in,
    A1、A2和A3各自独立地为CRA或N，所述取代基RA各自独立地选自氢，氘，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C8烷基、C3～C8环烷基，饱和或不饱和的被卤素、羟基、氨基或RC取代的C1～C8烷基，被卤素、羟基、氨基或RC取代的C3～C8环烷基，饱和或不饱和C1～C8烷氧基、C3～C8环烷氧基，饱和或不饱和的被卤素、羟基、氨基或RC取代的C1～C8烷氧基，被卤素、羟基、氨基或RC取代的C3～C8环烷氧基，-S(O)nRc，饱和或不饱和的取代或未取代的C1～C8酰基，NRCRD，A 1 , A 2 and A 3 are each independently CR A or N, and the substituent R A is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, saturated or unsaturated C 1 to C 8 alkyl substituted by halogen, hydroxyl, amino or R C , C 3 substituted by halogen, hydroxyl, amino or R C ~C 8 cycloalkyl, saturated or unsaturated C 1 ~ C 8 alkoxy, C 3 ~ C 8 cycloalkoxy, saturated or unsaturated C 1 ~ C substituted by halogen, hydroxyl, amino or R C 8 alkoxy, C 3 ~ C 8 cycloalkoxy substituted by halogen, hydroxyl, amino or R C , -S(O) n Rc, saturated or unsaturated substituted or unsubstituted C 1 ~ C 8 acyl ,NR C R D ,
    A4为O、S、N、C或连接键，A5、A6和A7各自独立地为O、S、N或C；并且A 4 is O, S, N, C or a connecting bond, and A 5 , A 6 and A 7 are each independently O, S, N or C; and
    当A4、A5、A6和A7为N或C时，各自可以独立地被RB取代；RB各自独立地选自氢，氘，卤素，氰基，羟基，-S(O)nRc，饱和或不饱和的C1～C8烷基、C3～C8环烷基，饱和或不饱和的被卤素、羟基、氨基或RC取代C1～C8烷基，被卤素、羟基、氨基或RC取代的C3～C8环烷基，饱和或不饱和的C1～C8烷氧基、C3～C8环烷氧基，饱和或不饱和的被卤素、羟基、氨基或RC取代C1～C8烷氧基，被卤素、羟基、氨基或RC取代的C3～C8环烷氧基，饱和或不饱和的取代或未取代的C1～C8酰基，饱和或不饱和的取代或未取代的C1～C8烷氧基羰基，饱和或不饱和的取代或未取代的C1～C8烷胺基羰基，NRCRD，When A 4 , A 5 , A 6 and A 7 are N or C, each can be independently replaced by RB ; RB is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -S(O) n Rc, saturated or unsaturated C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, saturated or unsaturated substituted by halogen, hydroxyl, amino or R C C 1 to C 8 alkyl, substituted by halogen , hydroxyl, amino or R C substituted C 3 ~ C 8 cycloalkyl, saturated or unsaturated C 1 ~ C 8 alkoxy, C 3 ~ C 8 cycloalkoxy, saturated or unsaturated substituted by halogen, Hydroxy, amino or R C substituted C 1 ~ C 8 alkoxy group, C 3 ~ C 8 cycloalkoxy group substituted by halogen, hydroxyl, amino or R C , saturated or unsaturated substituted or unsubstituted C 1 ~ C 8 acyl, saturated or unsaturated substituted or unsubstituted C 1 to C 8 alkoxycarbonyl, saturated or unsaturated substituted or unsubstituted C 1 to C 8 alkylaminocarbonyl, NR C R D ,
    其中，取代基RC和RD各自独立地选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C6烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基、-S(O)nRE或NRFRG取代C1～C6烷基，被卤素、羟基、-S(O)nRE或NRFRG取代的C3～C6环烷基，饱和或不饱和的C1～C6烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基、-S(O)nRE或NRFRG取代C1～C6烷氧基，被卤素、羟基、-S(O)nRE或NRFRG取代的C3～C6环烷氧基，其中RE、RF和RG各自独立地选自氢，氘，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C6烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基或氨基取代C1～C6烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C6烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基或氨基取代C1～C6烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基；Among them, the substituents R C and RD are each independently selected from hydrogen, halogen, cyano group, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated Saturated C 1 to C 6 alkyl substituted by halogen, hydroxyl, -S(O) n R E or NR F R G , C substituted by halogen, hydroxyl, -S(O) n R E or NR F R G 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 6 alkoxy, C 3 to C 6 cycloalkoxy, saturated or unsaturated by halogen, hydroxyl, -S(O) n R E Or NR FRG substituted C 1 ~ C 6 alkoxy group, C 3 ~ C 6 cycloalkoxy group substituted by halogen, hydroxyl, -S(O) n RE or NR FRG , where RE , R F and R G are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 6 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 to C 6 alkoxy, C 3 to C 6 Cycloalkoxy group, saturated or unsaturated C 1 to C 6 alkoxy group substituted by halogen, hydroxyl or amino group, C 3 to C 6 cycloalkoxy group substituted by halogen, hydroxyl group or amino group;
    R1和R2各自独立地为氢，饱和或不饱和的取代或未取代的C1～C8烷基、饱和或不饱和的取代或未取代的C3～C8环烷基、-OC(＝O)C1-8烷基、-OC(＝O)C3～C8环烷基、-C(＝O)OC1-8烷基、-C(＝O)OC3～C8环烷基、-S(O)nRc、饱和或不饱和的取代或未取代的C1～C8磺酰基、饱和或不饱和的取代或未取代的C1～C8酰基、C6～C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或杂芳基，其中所述“取代”是指选择性地含有1至4个选自羟基、卤素、氰基、磺酰基、氨基、-S(O)nRc、NRCRD、饱和或不饱和的C1～C8烷基、饱和或不饱和的C3～C8环烷基、饱和或不饱和的C1～C8烷氧基、饱和或不饱和的C3～C8环烷氧基、-OC(＝O)C1-8烷基、-OC(＝O)C3～C8环烷基、-C(＝O)OC1-8烷基、-C (＝O)OC3～C8环烷基、饱和或不饱和的C1～C8磺酰基、饱和或不饱和的C1～C8酰基、饱和或不饱和的C1～C8烷氧基羰基、C6～C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或杂芳基的取代基；R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 to C 8 alkyl, saturated or unsaturated substituted or unsubstituted C 3 to C 8 cycloalkyl, -OC (=O)C 1-8 alkyl, -OC(=O)C 3 to C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 to C 8 Cycloalkyl, -S(O) n Rc, saturated or unsaturated substituted or unsubstituted C 1 to C 8 sulfonyl group, saturated or unsaturated substituted or unsubstituted C 1 to C 8 acyl group, C 6 ~ C 14 aryl, 4 to 14 membered heterocycloalkyl or heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" means optionally containing 1 to 4 Selected from hydroxyl, halogen, cyano, sulfonyl, amino, -S(O) n Rc, NR CRD , saturated or unsaturated C 1 to C 8 alkyl, saturated or unsaturated C 3 to C 8 Cycloalkyl, saturated or unsaturated C 1 to C 8 alkoxy, saturated or unsaturated C 3 to C 8 cycloalkoxy, -OC(=O)C 1-8 alkyl, -OC(= O)C 3 ~ C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C (=O)OC 3 to C 8 cycloalkyl, saturated or unsaturated C 1 to C 8 sulfonyl, saturated or unsaturated C 1 to C 8 acyl, saturated or unsaturated C 1 to C 8 alkoxy Carbonyl, C 6 to C 14 aryl, 4 to 14 membered heterocycloalkyl or heteroaryl substituents containing 1 to 3 heteroatoms selected from N, O and S;
    或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的4至14元杂环烷基，取代或未取代的含有1至3个选自N、O和S的杂原子的5至14元杂芳基，其中所述“取代”是指选择性地含有1至4个选自氘，羟基，卤素，氰基，磺酰基，氨基，-S(O)nRc，NRCRD，C1～C8烷基，C3～C8环烷基，C1～C8烷氧基，C3～C8环烷氧基，-OC(＝O)C1-8烷基，-OC(＝O)C3～C8环烷基，-C(＝O)OC1-8烷基，-C(＝O)OC3～C8环烷基，被卤素、羟基、氨基或RH取代C1～C8烷基、C3～C8环烷基、C1～C8烷氧基、C3～C8环烷氧基的取代基，其中RH选自氢，氘，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C6烷基，C3～C6环烷基，-S(O)nRc，NRCRD，饱和或不饱和的被氘、卤素、羟基或氨基取代C1～C6烷基，被氘、卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C6烷氧基，C3～C6环烷氧基，饱和或不饱和的被氘、卤素、羟基或氨基取代C1～C6烷氧基，被氘、卤素、羟基或氨基取代的C3～C6环烷氧基；Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 4 to 14 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 14-membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to optionally containing 1 to 4 selected from deuterium, hydroxyl, halogen, and cyano groups, Sulfonyl, amino, -S(O) n Rc, NR C R D , C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkoxy, C 3 to C 8 ring Alkoxy group, -OC(=O)C 1-8 alkyl group, -OC(=O)C 3 to C 8 cycloalkyl group, -C(=O)OC 1-8 alkyl group, -C(=O )OC 3 ~ C 8 cycloalkyl, substituted by halogen, hydroxyl, amino or R H C 1 ~ C 8 alkyl, C 3 ~ C 8 cycloalkyl, C 1 ~ C 8 alkoxy, C 3 ~ C 8 cycloalkoxy substituents, wherein R H is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, - S(O) n Rc, NR C R D , saturated or unsaturated C 1 to C 6 alkyl group substituted by deuterium, halogen, hydroxyl or amino group, C 3 to C 6 ring substituted by deuterium, halogen, hydroxyl group or amino group Alkyl group, saturated or unsaturated C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 6 alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, C 3 to C 6 cycloalkoxy substituted by deuterium, halogen, hydroxyl or amino;
    R3为卤素，羟基，-S(O)nRc，NRCRD，饱和或不饱和的C1～C8烷基、C3～C8环烷基、C1～C8烷氧基、C3～C8环烷氧基，饱和或不饱和的被卤素、羟基、氨基或RH取代的C1～C8烷基、C3～C8环烷基、C1～C8烷氧基、C3～C8环烷氧基，其中取代基RH选自氢，氘，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C6烷基、C3～C6环烷基，饱和或不饱和的被卤素、羟基或氨基取代C1～C6烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C6烷氧基、C3～C6环烷氧基，饱和或不饱和的被卤素、羟基或氨基取代C1～C6烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基；R 3 is halogen, hydroxyl, -S(O) n Rc, NR C R D , saturated or unsaturated C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkoxy , C 3 ~ C 8 cycloalkoxy group, saturated or unsaturated C 1 ~ C 8 alkyl group substituted by halogen, hydroxyl, amino or R H , C 3 ~ C 8 cycloalkyl group, C 1 ~ C 8 alkyl group Oxygen group, C 3 to C 8 cycloalkoxy group, in which the substituent R H is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 6 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 6 alkoxy group, substituted by halogen, hydroxyl or amino group, C 3 to C 6 substituted by halogen, hydroxyl group or amino group cycloalkoxy;
    R4为氢或氘；R4 is hydrogen or deuterium;
    n为0、1或2的整数。n is an integer of 0, 1 or 2.
  2. 根据权利要求1所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐，其特征在于，The substituted pyrimidine hydrazide compound represented by formula I according to claim 1, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that,
    A1和A3为CRA，A2为N，所述取代基RA各自独立地选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基、C3～C6环烷基，饱和或不饱和的被卤素、羟基、氨基或RC取代的C1～C3烷基，被卤素、羟基、氨基或RC取代的C3～C6环烷基，饱和或不饱和C1～C3烷氧基、C3～C6环烷氧基，饱和或不饱和的被卤素、羟基、氨基或RC取代的C1～C3烷氧基，被卤素、羟基、氨基或RC取代的C3～C6环烷氧基，-S(O)nRc，饱和或不饱和的取代或未取代的C1～C3酰基，NRCRD。A 1 and A 3 are CR A , and A 2 is N. The substituents RA are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl, amino or R C , C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl, amino or R C group, saturated or unsaturated C 1 to C 3 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 3 alkoxy group substituted by halogen, hydroxyl, amino or R C , C 3 to C 6 cycloalkoxy substituted by halogen, hydroxyl, amino or R C , -S(O) n Rc, saturated or unsaturated substituted or unsubstituted C 1 to C 3 acyl, NR C R D .
  3. 根据权利要求1所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐，其特征在于，A1和A3为CRA，A2为N，并且所述取代基RA为氢。The substituted pyrimidine hydrazide compound represented by formula I according to claim 1, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that A 1 and A 3 are CRA and A 2 is N, and the substituent RA is hydrogen.
  4. 根据权利要求1所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐，其特征在于，A4为N、C或连接键，A5、A6和A7各自独立地为N或C，并且The substituted pyrimidine hydrazide compound represented by formula I according to claim 1, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that A 4 is N, C or a connecting bond, and A 5 , A 6 and A 7 are each independently N or C, and
    A4、A5、A6和A7各自独立地连接取代基RB，所述取代基RB各自独立地选自氢，卤素，氰基，羟基，氨基，-S(O)nRc，饱和或不饱和的C1～C3烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基、氨基或RC取代C1～C3烷基，被卤素、羟基、氨基或RC取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的 被卤素、羟基、氨基或RC取代C1～C3烷氧基，被卤素、羟基、氨基或R’取代的C3～C6环烷氧基，饱和或不饱和的取代或未取代的C1～C3酰基，饱和或不饱和的取代或未取代的C1～C3烷氧基羰基，NRCRD。A 4 , A 5 , A 6 and A 7 are each independently connected to a substituent RB , and the substituent RB is each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -S(O) n Rc, Saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl, amino or R C , substituted by halogen, hydroxyl, Amino or R C -substituted C 3 ~ C 6 cycloalkyl, saturated or unsaturated C 1 ~ C 3 alkoxy, C 3 ~ C 6 cycloalkoxy, saturated or unsaturated C 1 to C 3 alkoxy substituted by halogen, hydroxyl, amino or R C , C 3 to C 6 cycloalkoxy substituted by halogen, hydroxyl, amino or R', saturated or unsaturated substituted or unsubstituted C 1 to C 3 acyl group, saturated or unsaturated substituted or unsubstituted C 1 to C 3 alkoxycarbonyl group, NR C RD .
  5. 根据权利要求1所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐，其特征在于，The substituted pyrimidine hydrazide compound represented by formula I according to claim 1, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that,
    取代基RC和RD各自独立地选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基、-S(O)nRE或NRFRG取代C1～C3烷基，被卤素、羟基、-S(O)nRE或NRFRG取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基、-S(O)nRE或NRFRG取代C1～C3烷氧基，被卤素、羟基、-S(O)nRE或NRFRG取代的C3～C6环烷氧基；The substituents R C and R D are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated C 1 ~ C 3 alkyl substituted by halogen, hydroxyl, -S(O) n RE or NR F R G , C 3 ~ substituted by halogen, hydroxyl, -S(O) n RE or NR F R G C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy, saturated or unsaturated by halogen, hydroxyl, -S(O) n R E or NR F R G substituted C 1 ~ C 3 alkoxy group, C 3 ~ C 6 cycloalkoxy group substituted by halogen, hydroxyl, -S(O) n RE or NR F R G ;
    RE、RF和RG各自独立地选自氢，氘，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基。 RE , RF and RG are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino , saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or Unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 3 alkoxy group substituted by halogen, hydroxyl or amino group, C 3 to C 6 cycloalkoxy group substituted by halogen, hydroxyl group or amino group.
  6. 根据权利要求1所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐，其特征在于，A7为C。The substituted pyrimidine hydrazide compound represented by formula I according to claim 1, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that A 7 is C.
  7. 根据权利要求1所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐，其特征在于，The substituted pyrimidine hydrazide compound represented by formula I according to claim 1, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that,
    R1和R2各自独立地为氢、饱和或不饱和的取代或未取代的C1～C6烷基、饱和或不饱和的取代或未取代的C3～C6环烷基、-OC(＝O)C1-6烷基、-OC(＝O)C3～C6环烷基、-C(＝O)OC1-6烷基、-C(＝O)OC3～C6环烷基、饱和或不饱和的取代或未取代的C1～C6烷氧基、饱和或不饱和的取代或未取代的C3～C6环烷氧基、-S(O)nRc、NRCRD、饱和或不饱和的取代或未取代的C1～C6磺酰基、饱和或不饱和的取代或未取代的C1～C6酰基、C6～C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂芳基，其中所述“取代”是指选择性地含有1至4个选自羟基、卤素、氰基、磺酰基、氨基、-S(O)nRc、NRCRD、饱和或不饱和的C1～C6烷基、饱和或不饱和的C3～C6环烷基、-OC(＝O)C1-6烷基、-OC(＝O)C3～C6环烷基、-C(＝O)OC1-6烷基、-C(＝O)OC3～C6环烷基、饱和或不饱和的C1～C6磺酰基、饱和或不饱和的C1～C6酰基、C6～C10芳基、含有1至3个选自N、O和S的杂原子的6至10元杂环烷基或杂芳基的取代基；R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 to C 6 alkyl, saturated or unsaturated substituted or unsubstituted C 3 to C 6 cycloalkyl, -OC (=O)C 1-6 alkyl, -OC(=O)C 3 to C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 to C 6 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 to C 6 alkoxy, saturated or unsaturated substituted or unsubstituted C 3 to C 6 cycloalkoxy, -S(O) n Rc , NR CRD , saturated or unsaturated substituted or unsubstituted C 1 to C 6 sulfonyl group, saturated or unsaturated substituted or unsubstituted C 1 to C 6 acyl group , C 6 to C 10 aryl group, containing 5 to 10 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl , amino, -S(O) n Rc, NR CRD , saturated or unsaturated C 1 to C 6 alkyl, saturated or unsaturated C 3 to C 6 cycloalkyl, -OC(=O)C 1-6 alkyl, -OC(=O)C 3 to C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 to C 6 cycloalkyl, saturated Or unsaturated C 1 to C 6 sulfonyl group, saturated or unsaturated C 1 to C 6 acyl group, C 6 to C 10 aryl group, 6 to 3 heteroatoms selected from N, O and S. 10-membered heterocycloalkyl or heteroaryl substituents;
    或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的4至10元杂环烷基，取代或未取代的含有1至3个选自N、O和S的杂原子的5至10元杂芳基，其中所述“取代”是指选择性地含有1至4个选自羟基，卤素，氰基，磺酰基，氨基，-S(O)nRc，NRCRD，C1～C6烷基，C3～C6环烷基，C1～C6烷氧基，C3～C6环烷氧基，-OC(＝O)C1-6烷基，-OC(＝O)C3～C6环烷基，-C(＝O)OC1-6烷基，-C(＝O)OC3～C6环烷基，被卤素、羟基、氨基或RE取代C1～C6烷基、C3～C6环烷基、C1～C6烷氧基、C3～C6环烷氧基的取代基，其中RE选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C6烷基，C3～C6环烷基，-S(O)nRc，NRCRD，饱和或不饱和的被氘、卤素、羟基或氨基取代C1～C6烷基，被氘、卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C6烷氧基，C3～C6环烷氧基，饱和或不饱和的被氘、卤素、羟基或氨基取代C1～C6烷氧基，被氘、卤素、羟基或氨基取代的C3～C6环烷氧基。 Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 4 to 10 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 10 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl , amino, -S(O) n Rc, NR C R D , C 1 ~ C 6 alkyl, C 3 ~ C 6 cycloalkyl, C 1 ~ C 6 alkoxy, C 3 ~ C 6 cycloalkoxy Base, -OC(=O)C 1-6 alkyl, -OC(=O)C 3 ~ C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 to C 6 cycloalkyl, substituted by halogen, hydroxyl, amino or RE C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkoxy, C 3 to C 6 ring Substituent of alkoxy group, wherein RE is selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, -S(O) n Rc, NR CRD , saturated or unsaturated C 1 to C 6 alkyl substituted by deuterium, halogen , hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by deuterium, halogen, hydroxyl or amino, saturated Or unsaturated C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 6 alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by deuterium, halogen , hydroxyl- or amino-substituted C 3 to C 6 cycloalkoxy group.
  8. 根据权利要求1所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐，其特征在于，R3为卤素、-S(O)nRc，NRCRD，饱和或不饱和的C1～C6烷基、C3～C6环烷基，C1～C6烷氧基、C3～C6环烷氧基；饱和或不饱和的被卤素、羟基、氨基或RH取代的C1～C6烷基、C3～C6环烷基、C1～C6烷氧基、C3～C6环烷氧基，其中取代基RH选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基。The substituted pyrimidine hydrazide compound represented by formula I according to claim 1, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that R 3 is halogen, -S(O) n Rc, NR CRD , saturated or unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkoxy, C 3 to C 6 cycloalkoxy; saturated or Unsaturated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkoxy, C 3 to C 6 cycloalkoxy substituted by halogen, hydroxyl, amino or R H , The substituent R H is selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated by halogen, hydroxyl or Amino-substituted C 1 to C 3 alkyl group, C 3 to C 6 cycloalkyl group substituted by halogen, hydroxyl or amino group, saturated or unsaturated C 1 to C 3 alkoxy group, C 3 to C 6 cycloalkoxy group , saturated or unsaturated C 1 to C 3 alkoxy group substituted by halogen, hydroxyl or amino group, C 3 to C 6 cycloalkoxy group substituted by halogen, hydroxyl group or amino group.
  9. 根据权利要求1所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐，其特征在于，R1和R2各自独立地为氢、饱和或不饱和的取代或未取代的C1～C3烷基、饱和或不饱和的取代或未取代的C3～C6环烷基、-OC(＝O)C1-3烷基、-OC(＝O)C3～C6环烷基、-C(＝O)OC1-3烷基、-C(＝O)OC3～C6环烷基、-S(O)nRc、NRCRD、饱和或不饱和的取代或未取代的C1～C3磺酰基、饱和或不饱和的取代或未取代的C1～C3酰基，C6～C10芳基、含有1至3个选自N、O和S的杂原子的6至8元杂芳基，其中所述“取代”是指选择性地含有1至4个选自羟基、卤素、氰基、磺酰基、氨基、-S(O)nRc、NRCRD、-OC(＝O)C1-3烷基、-OC(＝O)C3～C6环烷基、-C(＝O)OC1-3烷基、-C(＝O)OC3～C6环烷基、饱和或不饱和的C1～C3烷基、饱和或不饱和的C3～C6环烷基、饱和或不饱和的C1～C3磺酰基、饱和或不饱和的C1～C3酰基、C6～C10芳基、含有1至3个选自N、O和S的杂原子的6至8元杂芳基的取代基；The substituted pyrimidine hydrazide compound represented by formula I according to claim 1, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that R 1 and R 2 are each independently hydrogen, Saturated or unsaturated substituted or unsubstituted C 1 to C 3 alkyl group, saturated or unsaturated substituted or unsubstituted C 3 to C 6 cycloalkyl group, -OC(=O)C 1-3 alkyl group, -OC(=O)C 3 to C 6 cycloalkyl, -C(=O)OC 1-3 alkyl, -C(=O)OC 3 to C 6 cycloalkyl, -S(O) n Rc , NR CRD , saturated or unsaturated substituted or unsubstituted C 1 to C 3 sulfonyl group, saturated or unsaturated substituted or unsubstituted C 1 to C 3 acyl group , C 6 to C 10 aryl group, containing 6- to 8-membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl , amino, -S(O) n Rc, NR C R D , -OC(=O)C 1-3 alkyl, -OC(=O)C 3 ~ C 6 cycloalkyl, -C(=O) OC 1-3 alkyl, -C(=O)OC 3 to C 6 cycloalkyl, saturated or unsaturated C 1 to C 3 alkyl, saturated or unsaturated C 3 to C 6 cycloalkyl, saturated Or unsaturated C 1 ~ C 3 sulfonyl group, saturated or unsaturated C 1 ~ C 3 acyl group, C 6 ~ C 10 aryl group, 6 to 6 to 3 heteroatoms selected from N, O and S Substituent of 8-membered heteroaryl;
    或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的5至10元杂环烷基，取代或未取代的含有1至3个选自N、O和S的杂原子的5至10元杂芳基，其中所述“取代”是指选择性地含有1至4个选自羟基、卤素、氰基、磺酰基、氨基、-S(O)nRc、NRCRD、C1～C3烷基、C3～C6环烷基C1～C3烷氧基、C3～C6环烷氧基，-OC(＝O)C1-3烷基，-OC(＝O)C3～C6环烷基，-C(＝O)OC1-3烷基，-C(＝O)OC3～C6环烷基，被卤素、羟基、氨基或RH取代C1～C3烷基、C3～C6环烷基、C1～C3烷氧基、C3～C6环烷氧基的取代基，其中RH选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基，C3～C6环烷基，-S(O)nRc，NRCRD，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基。Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 10 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl , amino, -S(O) n Rc, NR CRD , C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl , C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy , -OC(=O)C 1-3 alkyl, -OC(=O)C 3 ~ C 6 cycloalkyl, -C(=O)OC 1-3 alkyl, -C(=O)OC 3 ~C 6 cycloalkyl, substituted by halogen, hydroxyl, amino or R H C 1 ~ C 3 alkyl, C 3 ~ C 6 cycloalkyl, C 1 ~ C 3 alkoxy, C 3 ~ C 6 cycloalkyl The substituent of the oxygen group, where R H is selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, -S(O) n Rc, NR CRD , saturated or unsaturated C 1 to C 3 alkyl substituted by halogen, hydroxyl or amino , C 3 to C 6 cycloalkyl substituted by halogen, hydroxyl or amino, saturated or unsaturated C 1 ～C 3 alkoxy group, C 3 ～C 6 cycloalkoxy group, saturated or unsaturated C 1 ～C 3 alkoxy group, substituted by halogen, hydroxyl or amino group, C 3 ～ C 6 cycloalkoxy.
  10. 根据权利要求1所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐，其特征在于，R3为卤素、-S(O)nRc，NRCRD，饱和或不饱和的C1～C3烷基、C3～C6环烷基，C1～C3烷氧基、C3～C6环烷氧基；饱和或不饱和的被卤素、羟基、氨基或RF取代的C1～C3烷基、C3～C6环烷基、C1～C3烷氧基、C3～C6环烷氧基，其中取代基RH选自氢，卤素，氰基，羟基，氨基，饱和或不饱和的C1～C3烷基，C3～C6环烷基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷基，被卤素、羟基或氨基取代的C3～C6环烷基，饱和或不饱和的C1～C3烷氧基，C3～C6环烷氧基，饱和或不饱和的被卤素、羟基或氨基取代C1～C3烷氧基，被卤素、羟基或氨基取代的C3～C6环烷氧基。The substituted pyrimidine hydrazide compound represented by formula I according to claim 1, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that R 3 is halogen, -S(O) n Rc, NR CRD , saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy; saturated or Unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy substituted by halogen, hydroxyl, amino or RF , The substituent R H is selected from hydrogen, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated by halogen, hydroxyl or Amino-substituted C 1 to C 3 alkyl group, C 3 to C 6 cycloalkyl group substituted by halogen, hydroxyl or amino group, saturated or unsaturated C 1 to C 3 alkoxy group, C 3 to C 6 cycloalkoxy group , saturated or unsaturated C 1 to C 3 alkoxy group substituted by halogen, hydroxyl or amino group, C 3 to C 6 cycloalkoxy group substituted by halogen, hydroxyl group or amino group.
  11. 根据权利要求1所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐，其特征在于，R1和R2与连接它们的N原子一起形成的结构 选自以下基团中：

    The substituted pyrimidine hydrazide compound represented by formula I according to claim 1, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that R 1 and R 2 and the N atom connecting them structures formed together Selected from the following groups:

  12. 根据权利要求1所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐，其特征在于，所述取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐选自以下化合物中：



    The substituted pyrimidine hydrazide compound represented by formula I according to claim 1, each of which is an optical isomer, a prodrug or a pharmaceutically acceptable salt, characterized in that the substituted pyrimidine hydrazide compound, each of which Optical isomers, prodrugs or pharmaceutically acceptable salts are selected from the following compounds:



  13. 根据权利要求1至12任意一项所述的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐的制备方法，所述方法如下反应式1所示：
    According to the preparation method of the substituted pyrimidine hydrazide compound according to any one of claims 1 to 12, its respective optical isomer, prodrug or pharmaceutically acceptable salt, the method is shown in the following reaction formula 1:
    式III表示的羧酸化合物与式ⅠV表示的肼化合物进行缩合反应得到式Ⅰ所示的取代嘧啶酰肼类化合物；The carboxylic acid compound represented by formula III and the hydrazine compound represented by formula IV are subjected to a condensation reaction to obtain a substituted pyrimidine hydrazide compound represented by formula I;
    其中式III表示的羧酸化合物按照如下方法之一制备：The carboxylic acid compound represented by formula III is prepared according to one of the following methods:
    方法A
    Method A
    1)式V表示的甲基羰基化合物与草酸二甲酯反应得到式VI表示的化合物；1) The methyl carbonyl compound represented by formula V reacts with dimethyl oxalate to obtain the compound represented by formula VI;
    2)式VI表示的化合物与式X表示的肼化合物进行成环反应得到式VIⅠ表示的嘧啶化合物；2) The compound represented by formula VI and the hydrazine compound represented by formula X undergo a ring-forming reaction to obtain a pyrimidine compound represented by formula VII;
    3)式VIⅠ表示的嘧啶化合物经过水解反应得到式III表示的羧酸化合物；3) The pyrimidine compound represented by formula VII is subjected to a hydrolysis reaction to obtain the carboxylic acid compound represented by formula III;
    方法B
    Method B
    1)式V表示的甲基羰基化合物与草酸单烷基酯反应得到式VIIⅠ表示的 化合物，其中取代基R为甲基、乙基、异丙基、特丁基等；1) Methyl carbonyl compound represented by formula V and monoalkyl oxalate The reaction gives formula VIII represented by Compounds in which the substituent R is methyl, ethyl, isopropyl, tert-butyl, etc.;
    2)式VIIⅠ表示的化合物与式X表示的肼化合物进行成环反应得到式IX表示的嘧啶化合物；2) The compound represented by formula VIII and the hydrazine compound represented by formula X undergo a ring-forming reaction to obtain a pyrimidine compound represented by formula IX;
    3)式IX表示的嘧啶化合物经过水解反应脱除取代基R得到式III表示的羧酸化合物；3) The pyrimidine compound represented by Formula IX undergoes a hydrolysis reaction to remove the substituent R to obtain the carboxylic acid compound represented by Formula III;
    方法C
    Method C
    1)式V表示的甲基羰基化合物与尿素进行成环反应，得到式XI表示的化合物；1) The methyl carbonyl compound represented by formula V undergoes a cyclization reaction with urea to obtain the compound represented by formula XI;
    2)式XI表示的化合物与氯化试剂反应，如三氯氧磷、五氯化磷、氯化亚砜等，得到式XII表示的氯代化合物；2) The compound represented by formula XI reacts with a chlorinating reagent, such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, etc., to obtain the chlorinated compound represented by formula XII;
    3)式XII表示的氯代化合物与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，生成式XIII表示的化合物；3) Chlorinated compounds and boric acid compounds represented by formula XII Or react with the corresponding borate ester or trialkyl tin compound to generate the compound represented by formula XIII;
    4)式XIII表示的化合物脱去乙基形成羧酸基，得到式III表示的化合物；4) The compound represented by formula XIII removes the ethyl group to form a carboxylic acid group to obtain the compound represented by formula III;
    方法D
    Method D
    1)碳酸酯化合物与式X表示的肼化合物发生成环反应，得到式XIV表示的化合物；1) Carbonate compounds A cyclization reaction occurs with the hydrazine compound represented by formula X to obtain a compound represented by formula XIV;
    2)式XIV表示的化合物与氯化试剂反应，如三氯氧磷、五氯化磷、氯化亚砜等，得到式XV表示的氯代化合物；2) The compound represented by formula XIV reacts with a chlorinating reagent, such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, etc., to obtain a chlorinated compound represented by formula XV;
    3)式XV表示的氯代化合物与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，得到式III表示的化合物； 3) Chlorinated compounds and boric acid compounds represented by formula XV Or react with the corresponding borate ester or trialkyl tin compound to obtain the compound represented by formula III;
    方法E
    Method E
    1)嘧啶化合物与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，分离纯化后得到化合物 1) Pyrimidine compounds with boric acid compounds Or react with the corresponding borate ester or trialkyl tin compound, and obtain the compound after separation and purification
    2)化合物再与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，得到式III表示的化合物；2) Compounds Boric acid compound Or react with the corresponding borate ester or trialkyl tin compound to obtain the compound represented by formula III;
    方法F
    Method F
    1)嘧啶化合物与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，分离纯化后得到式XV表示的化合物； 1) Pyrimidine compounds with boric acid compounds Or react with the corresponding borate ester or trialkyl tin compound, and obtain the compound represented by formula XV after separation and purification;
    2)式XV表示的化合物再与硼酸化合物或相应的硼酸酯、或三烷基锡化合物反应，得到式III表示的化合物；2) The compound represented by formula XV is then mixed with a boric acid compound Or react with the corresponding borate ester or trialkyl tin compound to obtain the compound represented by formula III;
    式IV表示的肼化合物按照如下合成方法之一进行：The hydrazine compound represented by formula IV is synthesized according to one of the following methods:
    方法G
    Method G
    1)将BocNHNH2(叔丁氧羰基肼)溶解在如甲醇、乙醇等醇类溶剂中，然后加入酮类化合物(R1(C＝O)R1)或醛类化合物(R1(C＝O)H)反应，然后加入硼氢化钠加氢还原，纯化分离得到化合物 1) Dissolve BocNHNH 2 (tert-butoxycarbonyl hydrazine) in alcoholic solvents such as methanol, ethanol, etc., and then add ketone compounds (R 1 (C＝O)R 1 ) or aldehyde compounds (R 1 (C＝ O)H) reaction, then add sodium borohydride for hydrogenation reduction, and purify and isolate the compound.
    2)将化合物溶解在如N,N-二异丙基乙胺(DIEA)等胺类溶剂中，然后加入酮类化合物(R2(C＝O)R2)、醛类化合物(R2(C＝O)H)或相应的R2取代的环氧化合物进行反应，得到化合物 2) Combine the compound Dissolve in an amine solvent such as N,N-diisopropylethylamine (DIEA), then add ketone compounds (R 2 (C＝O)R 2 ) and aldehyde compounds (R 2 (C＝O) H) or the corresponding R 2 substituted epoxy compound reacts to obtain the compound
    3)将化合物溶解在如甲醇、乙醇等醇类溶剂中，然后加入过量的HCl的甲醇溶液，得到式IV表示的化合物的盐酸盐；3) Combine the compound Dissolve in alcoholic solvents such as methanol and ethanol, and then add excess HCl methanol solution to obtain the hydrochloride of the compound represented by formula IV;
    方法H
    Method H
    1)将取代的氨基化合物(HNR1R2)溶解在溶剂中，加入亚硝化试剂，所述亚硝化试剂选自亚硝酸叔丁酯、亚硝酸异丁酯，加热回流，减压浓缩得到中间体亚硝胺基化合物(R1N(R2)-N＝O)；1) Dissolve the substituted amino compound (HNR 1 R 2 ) in a solvent, add a nitrosating reagent selected from tert-butyl nitrite and isobutyl nitrite, heat to reflux, and concentrate under reduced pressure to obtain the intermediate Nitrosamine-based compound (R 1 N(R 2 )-N=O);
    2)将亚硝胺基化合物(R1N(R2)-N＝O)溶解在溶剂中，加入如氢化铝锂的氢化试剂进行加氢反应，得到式IV表示的化合物；2) Dissolve the nitrosamine-based compound (R 1 N (R 2 )-N=O) in a solvent, add a hydrogenation reagent such as lithium aluminum hydride to perform a hydrogenation reaction, and obtain the compound represented by Formula IV;
    其中取代基A1至A7，R1至R4的定义同权利要求1中所述。The substituents A 1 to A 7 and R 1 to R 4 have the same definitions as described in claim 1.
  14. 一种药物组合物，所述药物组合物包含治疗有效量的根据权利要求1至12任意一项所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接 受的盐和药学上可接受的赋形剂或载体。A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrimidine hydrazide compound represented by formula I according to any one of claims 1 to 12, each of its optical isomers, prodrugs or pharmaceuticals Available Acceptable salts and pharmaceutically acceptable excipients or carriers.
  15. 根据权利要求1至12任意一项所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐在制备AHR紊乱抑制剂中的用途。The use of the substituted pyrimidine hydrazide compound represented by formula I according to any one of claims 1 to 12, and its respective optical isomers, prodrugs or pharmaceutically acceptable salts in the preparation of AHR disorder inhibitors.
  16. 根据权利要求1至12任意一项所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐在制备治疗与AHR紊乱相关的肿瘤的药物中的应用。According to the substituted pyrimidine hydrazide compound represented by formula I according to any one of claims 1 to 12, each of its optical isomers, prodrugs or pharmaceutically acceptable salts is used in the preparation of drugs for the treatment of tumors related to AHR disorders. applications in.
  17. 一种治疗与AHR紊乱相关的肿瘤的方法，所述方法包括向需要其的受试者施用有效量的根据权利要求1至12任意一项所述的式Ⅰ表示的取代嘧啶酰肼类化合物，其各自旋光异构体，前药或药学上可接受的盐或根据权利要求13所述的药物组合物。 A method of treating tumors associated with AHR disorders, the method comprising administering an effective amount of a substituted pyrimidine hydrazide compound represented by formula I according to any one of claims 1 to 12 to a subject in need thereof, Each of its optical isomers, prodrugs or pharmaceutically acceptable salts or a pharmaceutical composition according to claim 13.
PCT/CN2023/090761 2022-04-29 2023-04-26 Substituted pyrimidine hydrazide compound, method for preparing same, and use thereof WO2023208018A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006084017A2 (en) * 2005-02-04 2006-08-10 Bristol-Myers Squibb Company Phenyl-substituted pyrimidine compounds useful as kinase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006084017A2 (en) * 2005-02-04 2006-08-10 Bristol-Myers Squibb Company Phenyl-substituted pyrimidine compounds useful as kinase inhibitors

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